Compounds containing carbon-carbon linker as gpr120 agonists

ABSTRACT

The present invention relates to compound of Formula (I) containing carbon-carbon linker, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, a prodrug, a polymorph, N-oxide, S-oxide, or a carboxylic acid isostere thereof; processes for their preparation; pharmaceutical compositions comprising said compounds; and their use for the treatment of the diseases or disorders mediated by GPR120 receptor.

FIELD OF THE INVENTION

The present invention relates to compounds containing carbon-carbonlinker represented by the compounds of Formula (I) (as describedherein); processes for their preparation; pharmaceutical compositionscomprising said compounds; and methods of using said compounds for thetreatment or prophylaxis of the diseases or disorders mediated by GPR120receptor.

BACKGROUND OF THE INVENTION

Metabolic diseases or disorders are caused by an abnormal metabolicprocess and may either be congenital due to an inherited enzymeabnormality, or acquired due to a disease of an endocrine organ orfailure of a metabolically important organ such as the liver or thepancreas.

Among the metabolic disorders, diabetes mellitus is the most prevalentand is considered to be one of the five leading causes of death in theworld (Diabetes Care, vol. 27, 2004, pp. 1047-1053). Diabetes mellitusis typically classified into two main subtypes: Type 1 and Type 2diabetes mellitus. Type 1 diabetes mellitus (otherwise known as InsulinDependent Diabetes Mellitus, IDDM), which generally occurs inadolescents under 20 years of age, is an auto-immune disease causing aninsulitis with the subsequent destruction of insulin-producing β-cellsof the pancreas. Further, in latent autoimmune diabetes in adults(LADA), β-cells are destroyed due to autoimmune attack. The subsequentlack of insulin leads to elevated levels of blood and urine glucose(hyperglycemia). Although the exact trigger for this autoimmune responseis not known, patients with Type 1 diabetes have high levels ofantibodies against pancreatic beta cells (hereinafter “beta cells”).However, it cannot be ascertained that all patients with high levels ofthese antibodies develop Type 1 diabetes. Type 2 diabetes mellitus ornon-insulin-dependent diabetes mellitus (NIDDM) is developed when humanmuscles, fat and liver cells are not able to respond normally to insulinthat body secretes. This inability to respond, otherwise known asinsulin resistance, may be due to restriction on the numbers of insulinreceptors on these cells, or a dysfunctional behaviour of signallingpathways within the cells, or both. Initially, the β-cells which areresponsible for the production of insulin, compensate for this insulinresistance by increasing their insulin secretion. However, graduallythese cells become unable to produce enough insulin to facilitate thenormal glucose homeostasis, causing the progression to Type 2 diabetes(Am J Med. 108(6), Supplement 1, 2000, pp. 2S-8S). Type 2 diabetes (T2D)is characterised by fasting hyperglycemia which occurs as an effect ofthe combined lesions of insulin resistance and β-cell dysfunction. Thereare two types of defects associated with the β-cells: the firstcomponent, an increase in the basal insulin release which usually occursin the presence of low, non-stimulatory glucose concentrations. Thesecond component is a failure to enhance the insulin release in responseto a hyperglycaemic challenge.

Obesity is another risk factor for developing metabolic diseases ordisorders such as diabetes, cardiovascular disorders, hypertension,hyperlipidemia and an increased mortality. Diabetes caused by insulinresistance and obesity are part of the “metabolic syndrome” which isdefined as the linkage between several diseases (also referred to assyndrome X, insulin-resistance syndrome, or deadly quartet). These oftenoccur in the same patients and are major risk factors for thedevelopment of Type 2 diabetes and cardiovascular diseases (Frontiers inEndocrinology, vol. 4, 2013, pp. 1-11). It has been suggested that thecontrol of lipid levels and/or glucose levels is required to treat type2 diabetes and cardiovascular diseases. Even though lifestyle changeslike exercise and healthy diet are regarded as the most efficient waysto prevent and manage the disease, pharmaceutical intervention isfrequently necessary.

Current treatment options for diabetes, particularly T2D include use ofhypoglycaemic agents and insulin. Metformin is one such hypoglycaemicagent, which is used in the treatment of Type 2 diabetes. It is, infact, one of the oldest drugs used for the treatment of T2D and itcontinues to remain the drug of choice despite associatedgastrointestinal (GI) side effects including anorexia, nausea, diarrhoeaand vomiting commonly associated with it. In fact, metformin should beused with caution in patients with renal impairment because of theslight risk of lactic acidosis. Sulfonylureas (SUs) e.g. glimepiride,glipizide, are insulin secretagogues, which act on β-cells to increaseinsulin release, are commonly used in the treatment of Type 2 diabetes.However, use of sulfonylureas is also associated with adverse effects inthat they increase the risk of hypoglycaemia and lead to weight gain.Insulin treatment also carries the same side-effects. Thiazolidinedionecompounds e.g. rosiglitazone, pioglitazone, are insulin sensitizerswhich bind to peroxisome proliferator-activated receptors (PPARs) incells and thereby increase the insulin sensitivity. Though,thiazolidinedione compounds have also been widely used, the enhancedrisks of cardiovascular disease and hepatotoxicity have resulted instringent limitations on their use. Relatively recently, regulatoryauthorities approved new classes of anti-diabetic agents such as GLP-1agonists (exenatide and liraglutide) and DPP-4 inhibitors (linagliptinand alogliptin).

It is a known fact that metabolic processes are regulated by fatty acidswhich are important biological molecules that serve both as a source ofenergy and as signalling molecules. Generally, it is believed that fattyacids produce their biological effects through interacting withintracellular targets including, for example, the family of peroxisomeproliferator-activated receptors (PPARs). However, in the recent yearsit has become clear that fatty acids also serve as agonists for a groupof cell surface G protein-coupled receptors (GPCRs). Free fatty acids(FFAs) have been demonstrated to act as ligands of several GPCRsincluding GPR40 (FFAR1), GPR43, GPR84, GPR119 and GPR120. One of theGPCR namely GPR40 facilitates glucose-stimulated insulin secretion frompancreatic β-cells, whereas the other GPCR namely GPR120 regulates thesecretion of glucagon-like peptide-1 (GLP-1) in the intestine, as wellas insulin sensitivity in macrophages. GPR120 is localized to intestinalenteroendocrine cells, such as colonic L cells. Certain research studiesconducted relative recently, identified that loss-of-function GPR120human variant is associated with obesity, diabetes and other insulinresistance, and related metabolic disorders, and also with inflammatorydisorders. These findings establish GPR120 as a potential target for thetreatment of diabetes, other metabolic disorders, and inflammatorydisorders as well (Trends Pharmacol Sci. vol. 32(9), 2011 pp. 543-550).

Various patent documents describe compounds which are reported to beGPR120 modulators. Examples of patent documents describing GPR120modulators include PCT Application Publications WO2008103500,WO2009038204, WO2010008831, WO2010048207, WO2010080537, WO2010104195,WO2011072132, WO2013139341 and WO2013185766; European Published PatentApplication EP2125758A1; US Published Patent Application US2011065739and U.S. Pat. No. 8,367,708.

Thus, in view of the role of GPR120 receptor in potentiating metabolicdisorders such as diabetes and related disorders, and also, inflammatorydisorders, there is a continuing need to develop compounds that act bymodulating the GPR120 receptor pathways.

SUMMARY OF THE INVENTION

In one aspect, the present invention relates to a compound of Formula(I) (as described herein), or a stereoisomer, a tautomer, apharmaceutically acceptable salt, a pharmaceutically acceptable solvate,a prodrug, a polymorph, N-oxide, S-oxide, or a carboxylic acid isosterethereof.

In another aspect, the present invention relates to a process for thepreparation of the compound of Formula (I) or a pharmaceuticallyacceptable salt thereof.

In a further aspect, the present invention relates to a pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof Formula (I) or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, or a pharmaceutically acceptable solvate thereof; andat least one pharmaceutically acceptable carrier or excipient.

In a further aspect, the present invention relates to a pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof Formula (I) or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, or a pharmaceutically acceptable solvate thereof; andone further therapeutically active agent and at least onepharmaceutically acceptable carrier or excipient.

In an aspect, the present invention relates to the compound of Formula(I) or a tautomer, a stereoisomer, a pharmaceutically acceptable salt ora pharmaceutically acceptable solvate thereof; for use as GPR120agonist.

In another further aspect, the present invention relates to a method formodulating GPR120 function in a cell, comprising contacting a cell withan effective amount of a compound of Formula (I) or a stereoisomer, atautomer or a pharmaceutically acceptable salt, or a pharmaceuticallyacceptable solvate thereof.

In yet another further aspect, the present invention relates to a methodfor the treatment or prophylaxis of a disease or a disorder mediated byGPR120, comprising administering to a subject in need thereof; atherapeutically effective amount of the compound of Formula (I) or astereoisomer, a tautomer, a pharmaceutically acceptable salt, or apharmaceutically acceptable solvate thereof.

In yet another aspect, the present invention relates to a compound ofFormula (I) or a stereoisomer, a tautomer, a pharmaceutically acceptablesalt, or a pharmaceutically acceptable solvate thereof; for use in thetreatment or prophylaxis of a disease or a disorder mediated by GPR120.

In a still further aspect, the present invention relates to use of thecompound of Formula (I) or a stereoisomer, a tautomer, apharmaceutically acceptable salt or a pharmaceutically acceptablesolvate thereof; in the manufacture of a medicament, for the treatmentor prophylaxis of a disease or a disorder mediated by GPR120.

In another further aspect, the present invention relates to use of thecompound of Formula (I) or a stereoisomer, a tautomer, or apharmaceutically acceptable salt or a pharmaceutically acceptablesolvate thereof; in combination with one further therapeutically activeagent for the treatment or prophylaxis of a disease or a disordermediated by GPR120.

These and other objectives and advantages of the present invention willbe apparent to those skilled in the art from the following description.

DETAILED DESCRIPTION OF THE INVENTION

It should be understood that the detailed description and specificexamples, while indicating embodiments of the invention, are given byway of illustration only, since various changes and modifications withinthe spirit and scope of the invention will become apparent to thoseskilled in the art.

One skilled in the art, based upon the definitions herein, may utilizethe present invention to its fullest extent. The following specificembodiments are to be construed as merely illustrative, and notlimitative of the remainder of the disclosure in any way whatsoever.

Except as defined herein, all the technical and scientific terms usedherein have the same meaning as commonly understood by one of ordinaryskill in the art to which the invention relates.

Definitions

For the purpose of the disclosure, listed below are definitions ofvarious terms used to describe the present invention. Unless otherwiseindicated, these definitions apply to the terms as they are usedthroughout the specification and the appended claims, eitherindividually or as part of a larger group. These definitions should notbe interpreted in the literal sense as they are not general definitions,and are relevant only for this application.

The singular forms “a”, “an” and “the” include plural aspects unless thecontext clearly dictates otherwise. For instance, the terms “a”, “an”and “the” refers to “one or more” when used in the subjectspecification, including the claims. Thus, for example, reference to “acompound” may include a plurality of such compounds, or reference to “adisease” or “a disorder” includes a plurality of diseases or disorders.

Also, use of “(s)” as part of a term, includes reference to the termsingly or in plurality, for example the term salt(s) indicates a singlesalt or more than one salt of the compound of formula (I).

The term “or” is generally employed in its sense including “and/or”unless the content clearly dictates otherwise.

A symbol (—) is used to indicate a point of attachment to the atom, forexample —COOH is attached through the carbon atom.

Unless indicated otherwise, the term “optionally substituted” when usedmeans “substituted or unsubstituted,” and therefore, the genericstructural formulae described herein encompasses compounds containingthe specified optional substituent as well as compounds that do notcontain the optional substituent. For example, the phrase “heteroaryl isoptionally substituted with one or more groups” encompassesunsubstituted heteroaryl ring, and heteroaryl ring substituted with oneor more groups as described.

Within the context of the present application and as used herein, theterm “unsaturated” means that a moiety has one or more units ofunsaturation.

Within the context of the present application and as used herein, theterm “partially unsaturated” refers to a ring moiety that includes atleast one double bond between ring atoms but is not aromatic.

The term “independently” when used in the context of selection ofsubstituents for a variable, it means that where more than onesubstituent is selected from a number of possible substituents, thosesubstituents can be the same or different.

As used herein, the term “halogen” refers to chlorine, fluorine, bromineor iodine atom.

As used herein, the term “(C₁-C₆)alkyl” or “alkyl” alone or as part of asubstituent group, refers to the radical of saturated aliphatic groups,including straight or branched-chain alkyl groups. A straight-chain orbranched chain alkyl has six or fewer carbon atoms in its backbone, forinstance, C₁-C₆ for straight chain and C₃-C₆ for branched chain. As usedherein, (C₁-C₆)alkyl refers to an alkyl group having from 1 to 6 carbonatoms. Representative examples of alkyl include, but are not limited to,methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl,sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylbutyl and3-methylbutyl. In the “(C₁-C₆)alkyl” group, one or more carbon atoms canbe optionally replaced with one or more heteroatoms independentlyselected from the group consisting of N, O and S.

Furthermore, unless stated otherwise, the alkyl group can beunsubstituted or substituted with one or more groups, for example, fromone to four groups, independently selected from the group consisting of(C₁-C₆)alkyl, (C₁-C₆)alkenyl, halogen, halo(C₁-C₆)alkyl, hydroxy,(C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy, (C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl,(C₆-C₁₀)aryloxy, heterocyclyl, heteroaryl, amino, cyano, nitro,—NH(C₁-C₆)alkyl, —N[(C₁-C₆)alkyl]_(z), —C(O)(C₁-C₆)alkyl,—C(O)O(C₁-C₆)alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆)alkyl, —C(O)N[(C₁-C₆)alkyl]₂and —C(O)NHSO₂(C₁-C₆)alkyl.

Examples of substituted alkyl include, but are not limited to,hydroxymethyl, 2-chlorobutyl, trifluoromethyl, aminoethyl or benzyl.

As used herein, the term “halo(C₁-C₆)alkyl” or “haloalkyl” refers toalkyl groups as defined above wherein one or more hydrogen atom of sameor different carbon atoms of the alkyl group are substituted with sameor different halogens. A monohalo(C₁-C₆)alkyl radical, for example, canhave a chlorine, bromine, iodine or fluorine atom. Dihalo orpolyhalo(C₁-C₆)alkyl radicals can have two or more of the same ordifferent halogen atoms. Representative examples of halo(C₁-C₆)alkylinclude, but are not limited to, chloromethyl, dichloromethyl,trichloromethyl, dichloroethyl, dichloropropyl, fluoromethyl,difluoromethyl, trifluoromethyl, pentafluoroethyl, heptafluoropropyl,difluorochloromethyl, dichlorofluoromethyl, difluoroethyl ordifluoropropyl.

As used herein, the term “(C₁-C₆)alkoxy” or “alkoxy” refers to a(C₁-C₆)alkyl having an oxygen radical attached thereto. The terms“(C₁-C₆)alkoxy” or “—O(C₁-C₆)-alkyl” or alkoxy wherever used in thisspecification have the same meaning. Representative examples of alkoxygroups include, but are not limited to, methoxy, ethoxy, propoxy,isopropoxy, n-butoxy, isobutoxy and tert-butoxy. Furthermore, unlessstated otherwise, the alkoxy groups can be unsubstituted or substitutedwith one or more groups. A substituted alkoxy refers to a (C₁-C₆)alkoxysubstituted with one or more groups, particularly one to four groupsindependently selected from the groups indicated above as thesubstituents for the alkyl group.

As used herein, the term (C₃-C₁₀)cycloalkyl” or “cycloalkyl” whetherused alone or as part of a substituent group, refers to a saturated orpartially unsaturated cyclic hydrocarbon radical including 1, 2 or 3rings and including a total of 3 to 10 carbon atoms; preferably 3 to 8carbon atoms forming the rings i.e. (C₃-C₁₀)cycloalkyl or(C₃-C₈)cycloalkyl group. The term cycloalkyl includes bridged, fused andspiro ring systems. For example, (C₃-C₁₀)cycloalkyl refers to acycloalkyl group having 3 to 10 (both inclusive) carbon atoms.Representative examples of cycloalkyl include, but are not limited to,cyclobutyl, cyclopentyl, cyclohexyl, 1,2,3,3a-tetrahydropentalene,adamantyl, norbornyl, tetrahydronaphthalene, bicyclo[2.1.0]pentane,bicyclo[4.2.0]octane, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]hept-2-ene,spiro[3.3]heptane, and the like. Unless stated otherwise,(C₄-C₈)cycloalkyl may be unsubstituted or substituted with one or moregroups independently selected from the group consisting of (C₁-C₆)alkyl,halogen, halo(C₁-C₆)alkyl, hydroxy, —O(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy,(C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, heterocyclyl, heteroaryl, amino andcyano.

The term “(C₆-C₁₀)aryl” or “aryl” as used herein refers to a monocyclicor bicyclic hydrocarbon groups having 6 to 10 ring carbon atoms, whereinat least one carbocyclic ring is having a π electron system. Examples of(C₆-C₁₀)aryl ring include, but are not limited to, phenyl or naphthyl.Unless indicated otherwise, aryl group may be unsubstituted orsubstituted with one or more groups. A substituted aryl refers to a(C₆-C₁₀)aryl substituted with one or more groups, preferably 1 to 7groups, and more preferably 1 to 3 groups independently selected fromthe group consisting of (C₁-C₆)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,halogen, halo(C₁-C₆)alkyl, hydroxy, —O—(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy,(C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, heterocyclyl, heteroaryl, amino andcyano. Aryl groups can be substituted in any desired position. Forexample, in monosubstituted aryl such as phenyl, the substituent can belocated in the 2-position, the 3-position, the 4-position or the5-position. If the phenyl carries two substituents, they can be locatedin 2,3-position, 2,4-position, 2,5-position, 2,6-position, 3,4-positionor 3,5-position. Examples of monosubstituted phenyl groups include, butare not limited to, 2-fluorophenyl, 2-ethoxyphenyl, 2-ethylphenyl,4-morpholinophenyl, (4-ethylpiperazin-1-yl)phenyl or4-(2-dimethylaminoethyl)phenyl. Examples of disubstituted phenyl groupsinclude, but are not limited to, 2,6-difluorophenyl or3,5-difluorophenyl.

As used herein, the term “heteroaryl”, whether used alone or as part ofa substituent group, refers to saturated or partially unsaturated 5- to12-membered, preferably 5- to 10-membered monocyclic or bicyclicaromatic ring system containing 1, 2, 3 or 4 heteroatoms independentlyselected from the group consisting of oxygen, nitrogen and sulfur atom.Representative examples of heteroaryls include, but are not limited to,furan, pyrrole, thiophene, imidazole, oxazole, thiazole, triazole,tetrazole, benzofuran, indole, benzoxazole, benzothiazole, isoxazole,triazine, purine, pyridine, pyrazine, quinoline, isoquinoline,phenazine, oxadiazole, pteridine, pyridazine, quinazolinyl, pyrimidine,isothiazole, quinoxaline (benzopyrazine), tetrazole,pyrido[2,3-b]pyrazine. The oxidized form of the ring nitrogen and sulfuratom contained in the heteroaryl to provide the corresponding N-oxide,S-oxide or S,S-dioxide is also encompassed in the scope of the presentinvention.

Furthermore, the heteroaryl groups can be unsubstituted or substitutedwith one or more groups; preferably 1 to 7 groups, more preferably 1 to3 groups independently selected from the group consisting of halogen,hydroxy, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₁-C₆)alkoxy,halo(C₁-C₆)alkoxy, (C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, heterocyclyl,heteroaryl, amino, cyano and oxo. The representative examples ofheteroaryl include, but are not limited to, pyrrole, pyrazole,imidazole, isothiazole, pyrazine, furan, thiophene, triazole,benzothiazole, benzofuran, indole, purine, pyridine, quinoline,isoquinoline, pyridazine, quinazolinyl, pyrimidine and azocine.

The term “heteroatom” as used herein, includes nitrogen (N), oxygen (O)and sulfur (S). Any heteroatom with unsatisfied valency is assumed tohave a hydrogen atom to satisfy the valency or when the heteroatom is N,it may be substituted with a group selected from (C₁-C₆)alkyl,—C(O)(C₁-C₆)alkyl, —C(O)O(C₁-C₆)alkyl or —S(O)₂(C₁-C₆)alkyl. Suitable(C₁-C₆)alkyl groups include, but are not limited to, methyl, ethyl,propyl, butyl, pentyl, hexyl, isopropyl or isobutyl.

As used herein, the term “heterocycloalkyl” refers to saturated orpartially unsaturated 5- to 12 membered, preferably 5- to 10-memberedmonocyclic or bicyclic ring containing at least one heteroatom,preferably, 1, 2, 3 or 4 heteroatoms independently selected from thegroup consisting of nitrogen, oxygen, and sulfur. The representativeexamples of heterocyclyl include, but are not limited to,tetrahydropyranyl, piperidinyl, piperidino, N-methylpiperidin-3-yl,piperazinyl, N-methylpyrrolidin-3-yl, 3-pyrrolidinyl, 2-pyrrolidon-I-yl,pyrrolidinyl, aziridinyl, pyrrolidino, piperazino, morpholinyl,morpholino, thiomorpholinyl, thiomorpholino, tetrahydrofuranyl,tetrahydrothiofuranyl, and pyranyl.

Furthermore, the heterocycloalkyl groups can be unsubstituted orsubstituted with one or more groups; preferably 1 to 7 groups, morepreferably 1 to 3 groups independently selected from the groupconsisting of halogen, hydroxy, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl,(C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy, (C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl,heterocyclyl, heteroaryl, amino, cyano and oxo

As used herein, the term “isotopic forms” or “isotopically labeledforms” is a general term used for isotopic forms of the compounds ofFormula (I), wherein one or more atoms of the compounds of Formula (I)are replaced by their respective isotopes. All isotopes of anyparticular atom or element as specified are contemplated within thescope of the compounds of the invention. Examples of isotopes that canbe incorporated into the compounds disclosed herein include, but are notlimited to, isotopes of hydrogen such as ²H (deuterium or D) and ³H,carbon such as ¹¹C, ¹³C and ¹⁴C, nitrogen such as ¹³N and ¹⁵N, oxygensuch as ¹⁵O, ¹⁷O and ¹⁸O, chlorine such as ³⁶Cl, fluorine such as ¹⁸Fand sulfur such as ³⁵S. Substitution with heavier isotopes, for example,replacing one or more key carbon-hydrogen bonds with carbon-deuteriumbond may show certain therapeutic advantages, resulting from longermetabolism cycles, (e.g., increased in vivo half life or reduced dosagerequirements), improved safety or greater effectiveness and hence, maybe preferred in certain circumstances.

In the context of the present invention, the term “the compounds of thepresent invention” or “the compounds encompassed in the presentinvention” are used interchangeably; and refer to the compounds ofFormula (I) and/or the compounds of Formula (IA) and/or the compounds ofFormula (IB) and/or the compounds of Formula (IC) as described herein,and encompass within its/their scope a stereoisomer, a tautomer, apharmaceutically acceptable salt, a pharmaceutically acceptable solvate,a prodrug, a polymorph or an N-oxide thereof. The compound(s) of thepresent invention can also be referred to herein as “the activecompound” or “the active ingredient”.

Within the context of the present invention and as used herein, the term“stereoisomer” is a general term used for all isomers of individualcompounds that differ only in the orientation of their atoms in space.The term stereoisomer includes mirror image isomers (enantiomers),mixtures of mirror image isomers (racemates, racemic mixtures),geometric (cis/trans, syn/anti or E/Z) isomers, and isomers of compoundswith more than one chiral center that are not mirror images of oneanother (diastereoisomers).

As used herein, the term “tautomer” refers to the coexistence of two ormore compounds that differ from each other only in the position of one(or more) mobile atoms and in electron distribution. For example, protontautomers (also known as prototropic tautomers) include interconversionsvia migration of a proton, such as keto-enol and imine-enaminetautomers.

Within the context of the present invention and as used herein, the term“pharmaceutically acceptable” means that the carrier, diluent,excipients, and/or salt must be compatible with the other ingredients ofthe formulation or composition, and not deleterious to the recipientthereof.

The term “pharmaceutically acceptable salt(s)” as used herein includes asalt or salts of the active compounds i.e. the compounds of Formula (I)and are prepared with suitable acids or bases, depending on theparticular substituents found on the compounds described herein.

As used herein, the term “pharmaceutically acceptable solvate” or“solvate(s)” describe a complex wherein the compound of Formula (I) ofthe present invention, is coordinated with a proportional amount of asolvent molecule. Specific solvates, wherein the solvent is water, arereferred to as hydrates.

As used herein, the term “prodrug” refers to a compound that is drugprecursor, which, when administered to a subject undergoestransformation through metabolic process or chemical transformation invivo to form an active compound, for example, a prodrug after beingbrought to the physiological pH or through enzyme action is converted toactive compounds, that is, compound of Formula (I) of the presentinvention. In context of the present invention prodrugs can be esters ofthe compound of Formula (I), which on metabolism can form an activecompound of Formula (I).

As used herein, the term “polymorph” or “polymorphic form” or“polymorphs” refers to crystals of the same compound that differs onlyin the arrangement and/or conformation of the molecule in the crystallattice.

As used herein, the term “N-oxide” refers to the oxide of the nitrogenatom of a nitrogen-containing heteroaryl or heterocycloalkyl. N-oxidecan be formed in the presence of an oxidizing agent for example peroxidesuch as m-chloro-perbenzoic acid or hydrogen peroxide. N-oxide refers toan amine oxide, also known as amine-N-oxide, and is a chemical compoundthat contains N→O bond.

As used herein, the term “S-oxide” refers to an oxide of the sulfur atom(S-oxide) or a dioxide of the sulfur atom (S,S-dioxide) of asulfur-containing heteroaryl or heterocycloalkyl. S-oxide andS,S-dioxides can be formed in the presence of an oxidizing agent, forexample, a peroxide such as m-chloro-perbenzoic acid or oxone.

As used herein, the term “carboxylic acid isostere” refers to afunctional group or a moiety that elicits similar physical, biologicaland/or chemical properties as a carboxylic acid moiety. Representativeexamples of carboxylic acid isostere include, but are not limited to:

wherein R is hydrogen or (C₁-C₃)alkyl.

The term “pharmaceutically acceptable carrier” as used herein means anontoxic, inert, solid, semi-solid, diluent, encapsulating material orformulation auxiliary of any type. A few examples of materials, whichcan serve as pharmaceutically acceptable carriers include, sugars suchas lactose, glucose, and sucrose; starches such as corn starch andpotato starch; cellulose and its derivatives such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; malt;gelatin; talc; as well as other non-toxic compatible lubricants such assodium lauryl sulfate and magnesium stearate, as well as coloringagents, releasing agents, coating agents, sweetening, flavoring andperfuming agents; preservatives and antioxidants can also be used in thecomposition, according to the judgment of the formulator.

As used herein, the term “a disease or a disorder mediated by GPR120” or“GPR120 mediated disease(s) or disorder(s)” refers to a disease or adisorder or a condition characterized by inappropriate, for example,less than or greater than normal GPR120 activity. A GPR120-mediateddisease or disorder may be completely or partially mediated byinappropriate GPR120 activity.

The term “metabolic disorder” as used herein refers to a disorderrelating to abnormality of metabolism. Accordingly, in the context ofthe present invention all the disorders relating to abnormality ofmetabolism are encompassed in the term “metabolic disorders”.

The term “metabolic syndrome” refers to a cluster of metabolicabnormalities including abdominal obesity, insulin resistance, glucoseintolerance, diabetes, hypertension and dyslipidemia. Theseabnormalities are known to be associated with an increased risk ofvascular events.

The term “diabetes mellitus” or “diabetes” refers to a chronic diseaseor condition, which occurs when the pancreas does not produce enoughinsulin, or when the body cannot effectively use the insulin itproduces. This leads to an increased concentration of glucose in theblood (hyperglycaemia). Two major forms of diabetes are Type 1 diabetes(Insulin-dependent diabetes mellitus) and Type 2 diabetes (Non-insulindependent diabetes mellitus (NIDDM)). Type 1 diabetes is an autoimmunecondition in which the insulin-producing β-cells of the pancreas aredestroyed which generally results in an absolute deficiency of insulin,the hormone that regulates glucose utilization. Type 2 diabetes oftenoccurs in the face of normal or even elevated levels of insulin and canresult from the inability of tissues to respond appropriately toinsulin. Other categories of diabetes include gestational diabetes (astate of hyperglycemia which develops during pregnancy) and “other”rarer causes (genetic syndromes, acquired processes such aspancreatitis, diseases such as cystic fibrosis, exposure to certaindrugs, viruses, and unknown causes).

The term “subject” as used herein refers to an animal, preferably amammal, and most preferably a human. The term “mammal” used hereinrefers to warm-blooded vertebrate animals of the class ‘mammalia’,including humans, characterized by a covering of hair on the skin and,in the female, milk-producing mammary glands for nourishing the young.The term mammal includes animals such as cat, dog, rabbit, bear, fox,wolf, monkey, deer, mouse, pig and human. In the context of the presentinvention, the phrase “a subject in need thereof” means a subject(patient) in need of the treatment for the disease or disorder that ismediated by GPR120. Alternatively, the phrase “a subject in needthereof” means a subject (patient) diagnosed having a disease or adisorder that is mediated by GPR120.

As used herein, the terms “treatment”, “treat”, “treating” and “therapy”and the like refer to alleviate, slow the progression, attenuation, orcure of existing diseases or condition (e.g. diabetes). Treatment alsoincludes curing, preventing development of or alleviating to someextent, one or more of the symptoms of the diseases or condition.

As used herein, the term “prophylaxis”, used interchangeably with theterms “prevention” or “preventing” means preventing or reducing theprobability of the occurrence of a clinical disease-state. Subjects areselected for preventative therapy based on factors that are known toincrease risk of suffering a clinical disease state or a condition,compared to the general population. “Prophylaxis” therapies can bedivided into (a) primary prevention and (b) secondary prevention.Primary prevention is defined as treatment in a subject that has not yetpresented with a clinical disease state or a condition, whereassecondary prevention is defined as preventing a second occurrence of thesame or similar clinical disease state.

The term “compound(s) for use” as used herein embrace any one or more ofthe following: (1) use of compound(s), (2) method of use of compound(s),(3) use in the treatment of, (4) the use for the manufacture ofpharmaceutical composition/medicament for treatment/treating or (5)method of treatment/treating/preventing/reducing/inhibiting comprisingadministering an effective amount of the compound of the presentinvention to a subject in need thereof.

As used herein, the term, “therapeutically effective amount” refers toan amount of a compound of Formula (I) or a pharmaceutically acceptablesalt thereof or a composition comprising a compound of Formula (I) or asalt thereof, effective in producing the desired therapeutic response ina subject suffering from a disease or disorder mediated by GPR120. Anexample of a disease or disorder mediated by GPR120 is diabetes such astype 2 diabetes. Particularly, the term “therapeutically effectiveamount” includes the amount of a compound (in the context of the presentinvention, the compound of Formula (I) or a pharmaceutically acceptablesalt thereof), when administered that induces a positive modification inthe disease or disorder to be treated or is sufficient to preventdevelopment of, or alleviate to some extent one or more of the symptomsof the disease or disorder being treated in a subject. In respect of thetherapeutic amount of the compound, consideration is also given that theamount of the compound used for the treatment of a subject is low enoughto avoid undue or severe side effects, within the scope of sound medicaljudgment. The therapeutically effective amount of the compound orcomposition will vary with the particular condition (in the context ofthe present invention, the disease or disorder that is mediated byGPR120) being treated, the age and physical condition of the subject,the severity of the condition being treated or prevented, the durationof the treatment, the nature of concurrent therapy, the specificcompound or composition employed, the particular pharmaceuticallyacceptable carrier utilized and other related factors.

As used herein, the term “GPR120 agonist(s)” refers to the compound(s)of Formula (I) of the present invention or a tautomer, a stereoisomer, apharmaceutically acceptable salt, a pharmaceutically acceptable solvate,a prodrug, a polymorph, an N-oxide, a S-oxide or a carboxylic acidisostere thereof; which binds to, activates, increases, stimulates,potentiates, sensitizes or upregulates GPR120 receptor and promotesinsulin sensitization.

In one aspect, the present invention relates to a compound of Formula(I),

wherein,Ring A is 3- to 10-membered cycloalkyl, 5- to 12-memberedheterocycloalkyl; (C₆-C₁₀)aryl or 5- to 12-membered heteroaryl; whereinthe heterocycloalkyl and the heteroaryl contain 1, 2, 3 or 4 heteroatomsindependently selected from the group consisting of N, O and S;Ring B and Ring C are independently selected from (C₆-C₁₀)aryl or 5- to12-membered heteroaryl containing 1, 2 or 3 heteroatoms independentlyselected from the group consisting of N, O and S;

X is

wherein

represents a point of attachment;R is hydrogen or (C₁-C₆)alkyl;R¹, R² and R³ at each occurrence are independently selected from thegroup consisting of hydrogen, halogen, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl,3- to 10-membered cycloalkyl and 5- to 12-membered heterocycloalkyl; ortwo R¹ are combined together with Ring A to form a 3- to 6-memberedcycloalkyl or 5- to 12-membered heterocycloalkyl;R⁴ and R⁷ are independently selected from the group consisting ofhydrogen and (C₁-C₆)alkyl;R⁵ and R⁶ are independently selected from the group consisting ofhydrogen, halogen and (C₁-C₆)alkyl;m, n and p are each integer independently selected from 1, 2 and 3;wherein,

(C₁-C₆)alkyl is unsubstituted or substituted with one or more groupsindependently selected from the group consisting of halogen, hydroxy,cyano, nitro, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, —O(C₁-C₆)alkyl,(C₃-C₈)cycloalkyl, (C₆-C₁₀)aryl, heterocycloalkyl and heteroaryl;

cycloalkyl is a 3- to 10-membered ring, which is unsubstituted orsubstituted with one or more groups independently selected from thegroup consisting of (C₁-C₆)alkyl, halogen, hydroxy, —O—(C₁-C₆)alkyl,(C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, heterocycloalkyl, heteroaryl, aminoand cyano;

heteroaryl is a 5- to 12-membered ring, which is unsubstituted orsubstituted with one or more groups independently selected from thegroup consisting of (C₁-C₆)alkyl, halogen, hydroxy, —O—(C₁-C₆)alkyl,(C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, heterocycloalkyl, heteroaryl, aminoand cyano;

heterocycloalkyl is a 5- to 12-membered ring, which is unsubstituted orsubstituted with one or more groups independently selected from thegroup consisting of (C₁-C₆)alkyl, halogen, hydroxy, —O—(C₁-C₆)alkyl,(C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, heterocycloalkyl, heteroaryl, aminoand cyano;

halogen is chlorine, bromine, iodine or fluorine;

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, apharmaceutically acceptable solvate, a prodrug, a polymorph, N-oxide,S-oxide, or a carboxylic acid isostere thereof.

In an embodiment, the present invention encompasses a compound ofFormula (I), wherein Ring A is unsubstituted or substituted 3- to10-membered cycloalkyl.

In one embodiment, the present invention encompasses a compound ofFormula (I), wherein Ring A is unsubstituted or substituted 5- to12-membered heterocycloalkyl containing 1, 2, 3 or 4 heteroatomsindependently selected from the group consisting of N, O and S.

In an embodiment, the present invention encompasses a compound ofFormula (I), wherein Ring A is unsubstituted or substituted(C₆-C₁₀)aryl.

In an embodiment, the present invention encompasses a compound ofFormula (I), wherein Ring A is 5- to 12-membered heteroaryl containing1, 2, 3 or 4 heteroatoms independently selected from the groupconsisting of N, O and S.

In an embodiment, the present invention encompasses a compound ofFormula (I), wherein Ring A is unsaturated or partially unsaturated(C₆-C₁₀)aryl.

In an embodiment, the present invention encompasses a compound ofFormula (I), wherein Ring A is unsaturated or partially unsaturated 5-to 12-membered heteroaryl.

In an embodiment, the present invention encompasses a compound ofFormula (I), wherein Ring A is

represents a point of attachment to Ring B.

In an embodiment, the present invention encompasses a compound ofFormula (I), wherein Ring B is unsubstituted, or substituted(C₆-C₁₀)aryl.

In an embodiment, the present invention encompasses a compound ofFormula (I), wherein Ring B is 5- to 12 membered heteroaryl containing1, 2 or 3 heteroatoms independently selected from the group consistingof N, O and S.

In an embodiment, the present invention encompasses a compound ofFormula (I), wherein Ring B is unsubstituted or substituted phenyl.

In an embodiment, the present invention encompasses a compound ofFormula (I), wherein Ring. B is unsubstituted or substituted phenyl, andR² is located at para position to Ring A and is as defined above; and nis 1.

In an embodiment, the present invention encompasses a compound ofFormula (I), wherein Ring B is phenyl and R² is halogen located at paraposition to Ring A and is as defined above; and n is 1.

In an embodiment, the present invention encompasses a compound ofFormula (I), wherein Ring C is unsubstituted or substituted(C₅-C₁₀)aryl.

In an embodiment, the present invention encompasses a compound ofFormula (I), wherein Ring C is 5- to 12-membered heteroaryl containing1, 2 or 3 heteroatoms independently selected from the group consistingof N, O and S.

In an embodiment, the present invention encompasses a compound ofFormula (I), wherein Ring C is unsubstituted or substituted phenyl, orunsubstituted or substituted 5- to 6-membered heteroaryl.

In an embodiment, the present invention encompasses a compound ofFormula (I), wherein Ring C is unsubstituted or substituted phenyl.

In an embodiment, the present invention encompasses a compound ofFormula (I), wherein Ring C is unsubstituted or substituted 5- to6-membered heteroaryl.

In an embodiment, the present invention encompasses a compound ofFormula (I), wherein Ring C is unsubstituted or substituted phenyl, orunsubstituted or substituted 6-membered heteroaryl.

In an embodiment, the present invention encompasses a compound ofFormula (I), wherein two R¹ are combined together with Ring A to form a3- to 6-membered cycloalkyl or 5- to 12-membered heterocycloalkyl.

In an embodiment, the present invention encompasses a compound ofFormula (I), wherein two R¹ are combined together with Ring A to form a3- to 6-membered cycloalkyl.

In an embodiment, the present invention encompasses a compound ofFormula (I), wherein Ring B is unsubstituted or substituted phenyl; RingC is unsubstituted or substituted phenyl, or unsubstituted orsubstituted 5- to 6-membered heteroaryl; R² is located at para positionto Ring A and is as defined above; R³ is hydrogen; and m & n are 1.

In an embodiment, the present invention encompasses a compound ofFormula (I), wherein Ring B is unsubstituted or substituted phenyl; RingC is unsubstituted or substituted phenyl, R² is halogen located at paraposition to Ring A; R³ is hydrogen; and m & n are 1.

In an embodiment, the present invention encompasses a compound ofFormula (I), wherein Ring B is unsubstituted or substituted phenyl; RingC is unsubstituted or substituted 5- to 6-membered heteroaryl; R² islocated at para position to Ring A and is as defined above; R³ ishydrogen; and m & n are 1.

In an embodiment, the present invention encompasses a compound ofFormula (I), wherein Ring B is unsubstituted or substituted (C₆-C₁₀)arylor 5- to 12-membered heteroaryl; Ring C is unsubstituted or substituted(C₅-C₁₀)aryl or 5- to 12-membered heteroaryl; Ring A is saturated orpartially unsaturated 5- to 12-membered bicyclic heteroaryl or 5- to12-membered bicyclic heterocycloalkyl; X, R′, R², R³, m, n & p are asdefined above.

In an embodiment, the present invention encompasses a compound ofFormula (I), wherein Ring B is unsubstituted or substituted (C₆-C₁₀)arylor 5- to 12-membered heteroaryl; Ring C is unsubstituted or substituted(C₆-C₁₀)aryl or 5- to 12-membered heteroaryl; Ring A is 5- to 6-memberedmonocyclic heteroaryl; R¹ is 3- to 10-membered cycloalkyl; X, R², R³, m,n & p are as defined above.

In an embodiment, the present invention encompasses a compound ofFormula (I), wherein X is

wherein

represents a point of attachment.

In an embodiment, the present invention encompasses a compound ofFormula (I), wherein X is

wherein R⁴ and R⁵ are as defined above, and

represents a point of attachment.

In an embodiment, the present invention encompasses a compound ofFormula (I), wherein X is

wherein R⁴, R⁵, R⁶ and R⁷ are as defined above, and

represents a point of attachment.

In another embodiment, the present invention encompasses a compound ofFormula (I), wherein R is hydrogen.

In another embodiment, the present invention encompasses a compound ofFormula (I), wherein R is (C₁-C₆)alkyl.

In an embodiment, the compound of Formula I encompasses a compound ofFormula IA;

wherein,

Ring. A is 3- to 10-membered cycloalkyl, 5- to 12-memberedheterocycloalkyl; (C₆-C₁₀)aryl or 5- to 12-membered heteroaryl, whereinthe heterocycloalkyl and the heteroaryl contain 1, 2, 3 or 4 heteroatomsindependently selected from the group consisting of N, O and S;Ring B and Ring C are independently selected from (C₆-C₁₀)aryl or 5- to12-membered heteroaryl containing 1, 2 or 3 heteroatoms independentlyselected from the group consisting of N, O and S;R is hydrogen or (C₁-C₆)alkyl;R¹, R² and R³ at each occurrence are independently selected from thegroup consisting of hydrogen, halogen, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl,3- to 10-membered cycloalkyl and 5- to 12-membered heterocycloalkyl;m, n and p are each an integer independently selected from 1, 2 and 3;wherein,

(C₁-C₆)alkyl is unsubstituted or substituted with one or more groupsindependently selected from the group consisting of halogen, hydroxy,cyano, nitro, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, —O(C₁-C₆)alkyl,(C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, heterocycloalkyl and heteroaryl;

cycloalkyl is a 3- to 10-membered ring, which is unsubstituted orsubstituted with one or more groups independently selected from thegroup consisting of (C₁-C₆)alkyl, halogen, hydroxy, —O—(C₁-C₆)alkyl,(C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, heterocycloalkyl, heteroaryl, aminoand cyano;

heteroaryl is a 5- to 12-membered ring, which is unsubstituted orsubstituted with one or more groups independently selected from thegroup consisting of (C₁-C₆)alkyl, halogen, hydroxy, —O—(C₁-C₆)alkyl,(C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, heterocycloalkyl, heteroaryl, aminoand cyano;

heterocycloalkyl is a 5- to 12-membered ring, which is unsubstituted orsubstituted with one or more groups independently selected from thegroup consisting of (C₁-C₆)alkyl, halogen, hydroxy, —O—(C₁-C₆)alkyl,(C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, heterocycloalkyl, heteroaryl, aminoand cyano;

halogen is chlorine, bromine, iodine or fluorine;

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, apharmaceutically acceptable solvate, a prodrug, a, polymorph, N-oxide,S-oxide, or a carboxylic acid isostere thereof.

In an embodiment, the compound of Formula (I) encompasses the compoundof Formula IA, wherein Ring A is 3- to 10-membered cycloalkyl, 5- to12-membered heterocycloalkyl; (C₆-C₁₀)aryl or 5- to 12-memberedheteroaryl;

Ring B is (C₆-C₁₀)aryl;Ring C is (C₆-C₁₀)aryl or 5- to 12-membered heteroaryl;R¹, R² and R³ at each occurrence are independently selected from thegroup consisting of hydrogen, halogen, (C₁-C₆)alkyl, 3- to 10-memberedcycloalkyl and 5- to 12-membered heterocycloalkyl;m, n and p are each integer independently selected from 1 or 2, andR is hydrogen or (C₁-C₆)alkyl.

In an embodiment, the compound of Formula (I) encompasses the compoundof Formula IA, wherein Ring A is 5- to 12-membered heterocycloalkyl,(C₆-C₁₀)aryl or 5- to 12-membered heteroaryl;

Ring B is (C₆-C₁₀)aryl;Ring C is (C₆-C₁₀)aryl or 5- to 6-membered heteroaryl;R¹ is hydrogen, halogen, (C₁-C₆)alkyl, 3- to 10-membered cycloalkyl or5- to 12-membered heterocycloalkyl;R² and R³ at each occurrence are independently selected from the groupconsisting of hydrogen, halogen and (C₁-C₆)alkyl;m, n and p are each integer independently selected from 1 or 2; andR is hydrogen or (C₁-C₆)alkyl.

In an embodiment, the compound of Formula (I) encompasses the compoundof Formula IA, wherein Ring A is 5- to 12-membered heterocycloalkyl or5- to 12-membered heteroaryl;

Ring B is phenyl;Ring C is phenyl or 5- to 6-membered heteroaryl;R¹ is hydrogen, halogen, (C₁-C₆)alkyl, 3- to 10-membered cycloalkyl or5- to 12-membered heterocycloalkyl;R² and R³ at each occurrence are independently selected from the groupconsisting of hydrogen and halogen;m, n and p are 1; andR is hydrogen or (C₁-C₆)alkyl.

In an embodiment, the compound of Formula (I) encompasses the compoundof Formula IA, wherein Ring A is 5- to 12-membered heterocycloalkyl or5- to 12-membered heteroaryl;

Ring B is phenyl;Ring C is phenyl or 6-membered heteroaryl;R¹ is hydrogen, halogen, (C₁-C₆)alkyl, 3- to 10-membered cycloalkyl or5- to 12-membered heterocycloalkyl;R² is halogen;R³ is hydrogen or halogen;m, n and p are 1; andR is hydrogen or (C₁-C₆)alkyl.

In an embodiment, the compound of Formula (I) encompasses the compoundof Formula IA, wherein Ring B is unsubstituted or substituted phenyl.

In an embodiment, the compound of Formula (I) encompasses the compoundof Formula IA, wherein Ring B is unsubstituted or substituted phenyl,and R² is located at para position to Ring A and is as defined above;and n is 1.

In an embodiment, the compound of Formula (I) encompasses the compoundof Formula IA, wherein Ring B is phenyl and R² is halogen located atpara position to Ring A; and n is 1.

In an embodiment, the compound of Formula (I) encompasses the compoundof Formula IA, wherein Ring C is unsubstituted or substituted phenyl, orunsubstituted or substituted 5- to 6-membered heteroaryl.

In an embodiment, the compound of Formula (I) encompasses the compoundof Formula IA, wherein Ring C is unsubstituted or substituted phenyl.

In an embodiment, the compound of Formula (I) encompasses the compoundof Formula IA, wherein Ring C is unsubstituted or substituted 5- to6-membered heteroaryl.

In an embodiment, the compound of Formula (I) encompasses the compoundof Formula IA, wherein Ring B is unsubstituted or substituted phenyl;Ring C is unsubstituted or substituted phenyl, or unsubstituted orsubstituted 5- to 6-membered heteroaryl; R² is located at para positionto Ring A and is as defined above; R³ is hydrogen; and m & n are 1.

In an embodiment, the compound of Formula (I) encompasses the compoundof Formula IA, wherein Ring B is unsubstituted or substituted phenyl;Ring C is unsubstituted or substituted phenyl, or unsubstituted orsubstituted 6-membered heteroaryl; R² is halogen located at paraposition to Ring A; R³ is hydrogen; and m & n are 1.

In another aspect, the compound of Formula I encompasses a compound ofFormula IB;

Ring A is 3- to 10-membered cycloalkyl, 5- to 12-memberedheterocycloalkyl; (C₆-C₁₀)aryl or 5- to 12-membered heteroaryl, whereinthe heterocycloalkyl and the heteroaryl contain 1, 2, 3 or 4 heteroatomsindependently selected from the group consisting of N, O and S;Ring B and Ring C are independently selected from the group consistingof (C₆-C₁₀)aryl or 5- to 12-membered heteroaryl containing 1, 2 or 3heteroatoms independently selected from the group consisting of N, O andS;R is hydrogen or (C₁-C₆)alkyl;R¹, R² and R³ at each occurrence are independently selected from thegroup consisting of hydrogen, halogen, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl,3- to 10-membered cycloalkyl, and 5- to 12-membered heterocycloalkyl;R⁴ is independently selected from hydrogen or (C₁-C₆)alkyl;R⁵ is independently selected from hydrogen, halogen or (C₁-C₆)alkyl;m, n and p are each an integer independently selected from 1, 2 and 3;wherein,

(C₁-C₆)alkyl is unsubstituted or substituted with one or more groupsindependently selected from the group consisting of halogen, hydroxy,cyano, nitro, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, —O(C₁-C₆)alkyl,(C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, heterocycloalkyl and heteroaryl;

cycloalkyl is a 3- to 10-membered ring, which is unsubstituted orsubstituted with one- or more groups independently selected from thegroup consisting of (C₁-C₆)alkyl, halogen, hydroxy, —O—(C₁-C₆)alkyl,(C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, heterocycloalkyl, heteroaryl, aminoand cyano;

heteroaryl is a 5- to 12-membered ring, which is unsubstituted orsubstituted with one or more groups independently selected from thegroup consisting of (C₁-C₆)alkyl, halogen, hydroxy, —O—(C₁-C₆)alkyl,(C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, heterocycloalkyl, heteroaryl, aminoand cyano;

heterocycloalkyl is a 5- to 12-membered ring, which is unsubstituted orsubstituted with one or more groups independently selected from thegroup consisting of (C₁-C₆)alkyl, halogen, hydroxy, —O—(C₁-C₆)alkyl,(C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, heterocycloalkyl, heteroaryl, aminoand cyano;

halogen is selected from chlorine, bromine, iodine or fluorine;

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, apharmaceutically acceptable solvate, a prodrug, a polymorph, N-oxide,S-oxide, or a carboxylic acid isostere thereof.

In an embodiment, the compound of Formula (I) encompasses the compoundof Formula IB, wherein Ring A is 3- to 10-membered cycloalkyl, 5- to12-membered heterocycloalkyl; (C₆-C₁₀)aryl or 5- to 12-memberedheteroaryl;

Ring B is (C₆-C₁₀)aryl;Ring C is (C₆-C₁₀)aryl and 5- to 12-membered heteroaryl;R¹, R² and R³ at each occurrence are independently selected from thegroup consisting of hydrogen, halogen, (C₁-C₆)alkyl, 3- to 10-memberedcycloalkyl and heterocycloalkyl;m, n and p are each integer independently selected from 1 or 2,R⁴ is independently selected from hydrogen or (C₁-C₆)alkyl;R⁵ is independently selected from hydrogen, halogen or (C₁-C₆)alkyl andR is hydrogen or (C₁-C₆)alkyl.

In an embodiment; the compound of Formula (I) encompasses the compoundof Formula IB, wherein Ring A is 5- to 10-membered heterocycloalkyl or5- to 10-membered heteroaryl;

Ring B is (C₆-C₁₀)aryl;Ring C is (C₆-C₁₀)aryl or 5- to 6-membered heteroaryl;R¹ is hydrogen, halogen, (C₁-C₆)alkyl, 3- to 10-membered cycloalkyl or5- to 12-membered heterocycloalkyl;R² and R³ at each occurrence are independently selected from the groupconsisting of hydrogen, halogen and (C₁-C₆)alkyl;m, n and p are each integer independently selected from 1 or 2;R⁴ and R⁵ are hydrogen, andR is hydrogen or (C₁-C₆)alkyl.

In an embodiment, the compound of Formula (I) encompasses the compoundof Formula IB, wherein Ring A is 5- to 10-membered heterocycloalkyl or5- to 10-membered heteroaryl;

Ring B is (C₆-C₁₀)aryl;Ring C is (C₆-C₁₀)aryl or 5- to 6-membered heteroaryl;R¹ is hydrogen, halogen, (C₁-C₆)alkyl, 3- to 10-membered cycloalkyl or5- to 12-membered heterocycloalkyl;R² and R³ at each occurrence are independently selected from the groupconsisting of hydrogen and halogen;m, n and p are 1;R⁴ and R⁵ are hydrogen, andR is hydrogen or (C₁-C₆)alkyl.

In an embodiment, the compound of Formula (I) encompasses the compoundof Formula IB, wherein Ring A is 5- to 12-membered heterocycloalkyl or5- to 12-membered heteroaryl;

Ring B is phenyl;Ring C is phenyl or 5- to 6-membered heteroaryl;R¹ is hydrogen, halogen, (C₁-C₆)alkyl, 3- to 10-membered cycloalkyl or5- to 12-membered heterocycloalkyl;R² and R³ are independently selected from the group consisting hydrogenand halogen;m, n and p are 1;R⁴ and R⁵ are hydrogen, andR is hydrogen or (C₁-C₆)alkyl.

In an embodiment, the compound of Formula (I) encompasses the compoundof Formula IB, wherein Ring A is 5- to 10-membered heterocycloalkyl or5- to 10-membered heteroaryl;

Ring B and Ring Care phenyl;R¹ is hydrogen, halogen, (C₁-C₆)alkyl, 3- to 10-membered cycloalkyl or5- to 12-membered heterocycloalkyl;R² and R³ are independently selected from hydrogen or halogen;m, n and p are 1;R⁴ and R⁵ are hydrogen, andR is hydrogen or (C₁-C₆)alkyl.

In an embodiment, the compound of Formula (I) encompasses the compoundof Formula IB, wherein Ring B is unsubstituted or substituted phenyl.

In an embodiment, the compound of Formula (I) encompasses the compoundof Formula IB, wherein Ring B is unsubstituted or substituted phenyl,and R² is located at para position to Ring A; and n is 1.

In an embodiment, the compound of Formula (I) encompasses the compoundof Formula IB, wherein Ring B is phenyl and R² is halogen located atpara position to Ring A; and n is 1.

In an embodiment, the compound of Formula (I) encompasses the compoundof Formula IB, wherein Ring C is unsubstituted or substituted phenyl, orunsubstituted or substituted 5- to 6-membered heteroaryl.

In an embodiment, the compound of Formula (I) encompasses the compoundof Formula IB, wherein Ring C is unsubstituted or substituted phenyl.

In an embodiment, the compound of Formula (I) encompasses the compoundof Formula IB, wherein Ring C is unsubstituted or substituted 5- to6-membered heteroaryl.

In an embodiment, the compound of Formula (I) encompasses the compoundof Formula IB, wherein Ring B is unsubstituted or substituted phenyl;Ring C is unsubstituted or substituted phenyl, or unsubstituted orsubstituted 5- to 6-membered heteroaryl; R² is located at para positionto Ring A and is as defined above; R³ is hydrogen; and m & n are 1.

In an embodiment, the compound of Formula (I) encompasses the compoundof Formula IB, wherein Ring B is unsubstituted or substituted phenyl;Ring C is unsubstituted or substituted phenyl, or unsubstituted orsubstituted 5- to 6-membered heteroaryl; R² is halogen located at paraposition to Ring A; R³ is hydrogen; and m & n are 1.

In an embodiment, the compound of Formula (I) encompasses the compoundof Formula IB, wherein Ring B is unsubstituted or substituted phenyl;Ring C is unsubstituted or substituted phenyl, or unsubstituted orsubstituted 6-membered heteroaryl; R² is halogen located at paraposition to Ring A; R³ is hydrogen; m & n are 1; and R⁴ and R⁵ arehydrogen.

In another aspect, the compound of Formula I encompasses a compound ofFormula IC,

wherein,Ring A is 3- to 10-membered cycloalkyl, 5- to 12-memberedheterocycloalkyl; (C₆- or 5- to 12-membered heteroaryl, wherein theheterocycloalkyl and the heteroaryl contain 1, 2, 3 or 4 heteroatomsindependently selected from the group consisting of N, O and S;Ring B and Ring C are independently selected from the group consistingof (C₆-C₁₀)aryl or 5- to 12-membered heteroaryl containing 1, 2 or 3heteroatoms independently selected from the group consisting of N, O andS;R is hydrogen or (C₁-C₆)alkyl;R¹, R² and R³ at each occurrence is independently selected from thegroup consisting of hydrogen, halogen, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl,3- to 10-membered cycloalkyl and 5- to 12-membered heterocycloalkyl;R⁴ and R⁷ are independently selected from hydrogen or (C₁-C₆)alkyl;R⁵ and R⁶ are independently selected from the group consisting ofhydrogen, halogen and (C₁-C₆)alkyl;m, n and pare each an integer independently selected from 1, 2 or 3;wherein,

(C₁-C₆)alkyl is unsubstituted or substituted with one or more groupsindependently selected from the group consisting of halogen, hydroxy,cyano, nitro, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, —O(C₁-C₆)alkyl,(C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, heterocyclyl and heteroaryl;

cycloalkyl is a 3- to 10-membered ring, which is unsubstituted orsubstituted with one or more groups independently selected from thegroup consisting of (C₁-C₆)alkyl, halogen, hydroxy, —O—(C₁-C₆)alkyl,(C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, heterocyclyl, heteroaryl, amino andcyano;

heteroaryl is a 5- to 12-membered ring, which is unsubstituted orsubstituted with one or more groups independently selected from thegroup consisting of (C₁-C₆)alkyl, halogen, hydroxy, —O—(C₁-C₆)alkyl,(C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, heterocycloalkyl, heteroaryl, aminoand cyano;

heterocycloalkyl is a 5- to 12-membered ring, which is unsubstituted orsubstituted with one or more groups independently selected from thegroup consisting of (C₁-C₆)alkyl, halogen, hydroxy, —O—(C₁-C₆)alkyl,(C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, heterocycloalkyl, heteroaryl, aminoand cyano;

halogen is selected from chlorine, bromine, iodine or fluorine;

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, apharmaceutically acceptable solvate, a prodrug, a polymorph, N-oxide,S-oxide, or a carboxylic acid isostere thereof.

In an embodiment, the compound of Formula (I) encompasses the compoundof Formula IC, wherein Ring A is 3- to 10-membered cycloalkyl, 5- to12-membered heterocycloalkyl; (C₆-C₁₀)aryl or 5- to 12-memberedheteroaryl;

Ring B is (C₆-C₁₀)aryl;Ring C is (C₆-C₁₀)aryl or 5- to 12-membered heteroaryl;R¹, R² and R³ at each occurrence are independently selected from thegroup consisting of hydrogen, halogen, (C₁-C₆)alkyl, 3- to 10-memberedcycloalkyl and heterocycloalkyl;m, n and p are each integer independently selected from 1 or 2,R⁴ and R⁷ are independently selected from hydrogen or (C₁-C₆)alkyl;R⁵ and R⁶ are independently selected from hydrogen or halogen; andR is hydrogen or (C₁-C₆)alkyl.

In an embodiment, the compound of Formula (I) encompasses the compoundof Formula IC, wherein Ring A is 3- to 8-membered cycloalkyl, 5- to10-membered heterocycloalkyl or 5- to 10-membered heteroaryl;

Ring B is (C₆-C₁₀)aryl;Ring C is (C₆-C₁O)aryl or 5- to 6-membered heteroaryl;R¹ is hydrogen, halogen, (C₁-C₆)alkyl, 3- to 10-membered cycloalkyl or5- to 12-membered heterocycloalkyl;R² and R³ at each occurrence are independently selected from the groupconsisting of hydrogen, halogen and (C₁-C₆)alkyl;m, n and p are each integer independently selected from 1 or 2;R⁴ and R⁷ are hydrogen;R⁵ and R⁶ are independently selected from hydrogen or halogen; andR is hydrogen or (C₁-C₆)alkyl.

In an embodiment, the compound of Formula (I) encompasses the compoundof Formula IC, wherein Ring A is 5- to 10-membered heterocycloalkyl or5- to 10-membered heteroaryl;

Ring B is phenyl;Ring C is phenyl or 5- to 6-membered heteroaryl;R¹ is hydrogen, halogen, (C₁-C₆)alkyl, 3- to 10-membered cycloalkyl or5- to 12-membered heterocycloalkyl;R² and R³ are independently selected from hydrogen or halogen;m, n and p are 1;R⁴ and R⁷ are hydrogen;R⁵ and R⁶ are halogen; andR is hydrogen or (C₁-C₆)alkyl.

In an embodiment, the compound of Formula (I) encompasses the compoundof Formula IC, wherein Ring A is 5- to 10-membered heterocycloalkyl or5- to 10-membered heteroaryl;

Ring B and Ring C are phenyl;R¹ is hydrogen, halogen, (C₁-C₆)alkyl, 3- to 10-membered cycloalkyl or5- to 12-membered heterocycloalkyl;R² and R³ are hydrogen or halogen;m, n and p are 1;R⁴ and R⁷ are hydrogen;R⁵ and R⁶ are halogen; andR is hydrogen or (C₁-C₆)alkyl.

In an embodiment, the compound of Formula (I) encompasses the compoundof Formula IC, wherein Ring B is unsubstituted or substituted phenyl.

In an embodiment, the compound of Formula (I) encompasses the compoundof Formula IC, wherein Ring B is unsubstituted or substituted phenyl,and R² is located at para position to Ring A and is as defined above;and n is 1.

In an embodiment, the compound of Formula (I) encompasses the compoundof Formula IC, wherein Ring B is phenyl and R² is halogen located atpara position to Ring A; and n is 1.

In an embodiment, the compound of Formula (I) encompasses the compoundof Formula IC, wherein Ring C is unsubstituted or substituted phenyl, orunsubstituted or substituted 5- to 6-membered heteroaryl.

In an embodiment, the compound of Formula (I) encompasses the compoundof Formula IC, wherein Ring C is unsubstituted or substituted phenyl.

In an embodiment, the compound of Formula (I) encompasses the compoundof Formula IC, wherein Ring C is unsubstituted or substituted 5- to6-membered heteroaryl.

In an embodiment, the compound of Formula (I) encompasses the compoundof Formula IC, wherein Ring B is unsubstituted or substituted phenyl;Ring C is unsubstituted or substituted phenyl, or unsubstituted orsubstituted 5- to 6-membered heteroaryl; R² is located at para positionto Ring A and is as defined above; R³ is hydrogen; and m & n are 1.

In an embodiment, the compound of Formula (I) encompasses the compoundof Formula IC, wherein Ring B is unsubstituted or substituted phenyl;Ring C is unsubstituted or substituted phenyl, or unsubstituted orsubstituted 5- to 6-membered heteroaryl; R² is halogen located at paraposition to Ring A; R³ is hydrogen; and m & n are 1.

In an embodiment, the compound of Formula (I) encompasses the compoundof Formula IC, wherein Ring B is unsubstituted or substituted phenyl;Ring C is unsubstituted or substituted phenyl, or unsubstituted orsubstituted 5- to 6-membered heteroaryl; R² is halogen located at paraposition to Ring A; R³ is hydrogen; m & n are 1; R⁴ and R⁷ are hydrogen;and R⁵ and R⁶ are halogen.

In an embodiment, the compound of Formula (I) encompasses the compoundof Formula ID,

wherein,Ring A is 3- to 10-membered cycloalkyl, 5- to 12-memberedheterocycloalkyl; (C₅-C₁₀)aryl or 5- to 12-membered heteroaryl; whereinthe heterocycloalkyl and the heteroaryl contain 1, 2, 3 or 4 heteroatomsindependently selected from the group consisting of N, O and S;Ring B and Ring C are independently selected from (C₆-C₁₀)aryl or 5- to12-membered heteroaryl containing 1, 2 or 3 heteroatoms independentlyselected from the group consisting of N, O and S;

X is

wherein

represents a point of attachment;R is hydrogen or (C₁-C₆)alkyl;R¹, R² and R³ at each occurrence are independently selected from thegroup consisting of hydrogen, halogen, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl,3- to 10-membered cycloalkyl and 5- to 12-membered heterocycloalkyl;R⁴ and R⁷ are independently selected from the group consisting ofhydrogen and (C₁-C₆)alkyl;R⁵ and R⁶ are independently selected from the group consisting ofhydrogen, halogen and (C₁-C₆)alkyl;m, n and p are each integer independently selected from 1, 2 and 3;wherein,

(C₁-C₆)alkyl is unsubstituted or substituted with one or more groupsindependently selected from the group consisting of halogen, hydroxy,cyano, nitro, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, —O(C₁-C₆)alkyl,(C₃-C₈)cycloalkyl, (C₆-C₁₀)aryl, heterocycloalkyl and heteroaryl;

cycloalkyl is a 3- to 10-membered ring, which is unsubstituted orsubstituted with one or more groups independently selected from thegroup consisting of (C₁-C₆)alkyl, halogen, hydroxy, —O—(C₁-C₆)alkyl,(C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, heterocycloalkyl, heteroaryl, aminoand cyano;

heteroaryl is a 5- to 12-membered ring, which is unsubstituted orsubstituted with one or more groups independently selected from thegroup consisting of (C₁-C₆)alkyl, halogen, hydroxy, —O—(C₁-C₆)alkyl,(C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, heterocycloalkyl, heteroaryl, aminoand cyano;

heterocycloalkyl is a 5- to 12-membered ring, which is unsubstituted orsubstituted with one or more groups independently selected from thegroup consisting of (C₁-C₆)alkyl, halogen, hydroxy, —O—(C₁-C₆)alkyl,(C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, heterocycloalkyl, heteroaryl, aminoand cyano;

halogen is chlorine, bromine, iodine or fluorine;

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, apharmaceutically acceptable solvate, a prodrug, a polymorph, N-oxide,S-oxide, or a carboxylic acid isostere thereof.

Representative compounds of Formula (I) encompassed in accordance withthe present invention include:

-   4-(5-((5-Fluoro-2-(6-methoxypyridin-3-yl)phenyl)ethynyl)pyridin-2-yl)butanoic    acid;-   4-(5-(5-Fluoro-2-(6-methoxypyridin-3-yl)phenethyl)pyridin-2-yl)butanoic    acid;-   4-(5-((5-Fluoro-2-(5-methylthiophen-2-yl)phenyl)ethynyl)pyridin-2-yl)butanoic    acid;-   4-(5-(5-Fluoro-2-(5-methylthiophen-2-yl)phenethyl)pyridin-2-yl)butanoic    acid;-   4-(4-(1,1-Difluoro-2-(5-fluoro-2-(5-methylthiophen-2-yl)phenyl)ethyl)phenyl)butanoic    acid;-   4-(4-(1,1-Difluoro-2-(5-fluoro-2-(5-(1-methylcyclopropyl)thiophen-2-yl)phenyl)ethyl)phenyl)butanoic    acid;-   4-(4-(1,1-Difluoro-2-(4-fluoro-4′-methyl-[1,1′-biphenyl]-2-yl)ethyl)phenyl)butanoic    acid;-   4-(4-(2-(2-(5-Cyclopropylthiophen-2-yl)-5-fluorophenyl)-1,1-acid;-   4-(4-(2-(2-(2,3-Dihydrobenzofuran-5-yl)-5-fluorophenyl)-1,1-difluoroethyl)phenyl)butanoic    acid;-   4-(4-(2-(4′-Cyclopropyl-4-fluoro-[1,1′-biphenyl]-2-yl)-1,1-difluoroethyl)phenyl)butanoic    acid;-   4-(4-((2-(5-(1-Cyanocyclopropyl)thiophen-2-yl)-5-fluorophenyl)ethynyl)phenyl)butanoic    acid;-   4-(4-(5-fluoro-2-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)phenethyl)phenyl)butanoic    acid;-   4-(4-(2-(5-cyclopropylthiophen-2-yl)-5-fluorophenethyl)phenyl)butanoic    acid;-   4-(4-(5-fluoro-2-(5-(1-methylcyclopropyl)thiophen-2-yl)styryl)phenyl)butanoic    acid;-   4-(4-(2-(5-(1-cyanocyclopropyl)thiophen-2-yl)-5-fluorostyryl)phenyl)butanoic    acid;-   4-(4-(5-fluoro-2-(4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)styryl)phenyl)butanoic    acid;-   4-(4-(5-fluoro-2-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)styryl)phenyl)butanoic    acid;-   4-(4-((2-(5-cyclopropylthiophen-2-yl)-5-fluorophenyl)ethynyl)phenyl)butanoic    acid;-   4-(4-((5-fluoro-2-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)phenyl)ethynyl)phenyl)butanoic    acid;-   4-(4-(1,1-difluoro-2-(5-fluoro-2-(6-methoxypyridin-3-yl)phenyl)ethyl)phenyl)butanoic    acid;-   4-(4-(1,1-difluoro-2-(5-fluoro-2-(5,6,7,8-tetrahydronaphthalen-2-yl)phenyl)ethyl)phenyl)butanoic    acid;-   4-(4-(2-(2-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-5-fluorophenyl)-1,1-difluoroethyl)phenyl)butanoic    acid;    or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or    a pharmaceutically acceptable solvate thereof.    Specific compounds encompassed in the present invention can also be    found in the examples set out below.

The compounds of the present invention also include stereoisomeric andtautomeric forms and mixtures thereof and their pharmaceuticallyacceptable salts, pharmaceutically acceptable solvates, pharmaceuticallyacceptable prodrugs, pharmaceutically acceptable polymorphs and N-oxidesthereof.

In an aspect of the present invention, there are provided processes forthe preparation of the compounds of Formula (I) or pharmaceuticallyacceptable salts thereof.

The compounds of Formula (I) can be prepared by various methodsincluding using methods well known to a person skilled in the art.Examples of processes for the preparation of a compound of Formula (I)are described below and illustrated in the following schemes but are notlimited thereto. It will be appreciated by the persons skilled in theart that within the processes described herein, the order of thesynthetic steps employed may be varied and will depend inter alia onfactors such as the nature of functional groups present in a particularsubstrate and the protecting group strategy (if any) to be adopted.Clearly, such factors will also influence the choice of reagents such asbases, solvents, coupling agents to be used in the reaction steps.

The reagents, reactants and intermediates used in the followingprocesses are either commercially available or can be prepared accordingto standard procedures known in the art, for instance those reported inthe literature references.

In the following schemes and the description of the processes, thestarting compounds and the intermediates used for the synthesis of thecompounds of the present invention are referred to by the symbols 1a,1b, 1c, 1d, 1e, 1f, 1g, 1h, 1i, 1j, 1k, 1l, 1m, 1n, 2a, 2b, 2c, 2d, 2e,2f, 2g, 2h, 2i, 2j, 2j, 2k, 2l, 2m, 2n, 3a, 3b, 3c, 3d, 3e, 3f and 3grespectively, for ease of reference.

Unless stated otherwise, throughout the process description, thecorresponding substituent groups in the various formulae representingstarting compounds and/or intermediates have the same meaning as that ofthe compound of Formula I as described in one or more embodiments of theinvention.

Processes for the preparation of the compounds of Formula I in one ormore embodiments as described above, are depicted in schemes, aspresented herein below. For ease of reference, the reaction steps shownin the Schemes, are referred to by using general symbols namely 1.1,1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 1.10, 1.11, 2.1, 2.2, 2.3, 2.4,2.5, 2.6, 2.7, 2.8, 2.9, 2.10, 2.11, 3.1, 3.2, 3.3, 3.4 and 3.5respectively.

The compounds of the present invention were purified by either flashchromatography (ISCO Combiflash® chromatography instrument from TeledyneIsco, Inc.) or silica gel column chromatography. Mass spectrometry (MS)was performed using a Esquire 4000 Mass spectrometer (from BrukerDaltonics), Nuclear magnetic resonance spectroscopy (NMR) was performedusing a Bruker Avance NMR spectrometer (for the ¹H NMR spectra acquiredat 300 MHz and 500 MHz) and the chemical shifts were reported in δ(ppm).

Scheme 1:

Preparation of the compound of Formula I [referred to in Scheme 1 ascompound 1a, 1b, 1c, 1d, 1e, 1f, 1g, 1h, 1i, 1j, 1k, 1l, 1m and 1nwherein R¹, R², R³, m, n and p are as defined in any one of theembodiments of the compound of Formula I as described herein].

Step 1.1:

Compound 1a (wherein R⁵ is hydrogen or methyl; R³ and p are as definedin any one of the embodiments of the compound of Formula I describedherein) is reacted with 0.25 equivalents of NaBH₄ (Sodium borohydride)and a solvent mixture THF:Ethanol (40:28) at a temperature of −5° C. for6 hours to obtain the compound 1b (wherein R⁵, R³ and p are as definedfor compound 1a).

Step 1.2:

In this process step, the compound 1b is treated with 0.4 equivalents ofPBr₃ (Phosphorus tribromide) at a temperature of 0° C. for 0.5 hours toobtain the compound 1c (wherein R⁵; R³ and p are as defined for compound1a).

Step 1.3:

In this process step, the compound 1c is treated with NaBH₄ (Sodiumborohydride) and a solvent such as methanol at a temperature of −5° C.for 0.5 hours to obtain the compound 1d (wherein R⁵; R³ and p are asdefined for compound 1a).

Step 1.4:

In this process step, the compound 1d is subjected to Sonogashiracoupling. Compound 1d is treated with a compound of formula 1e, ≡—COOEtin the presence of copper(I) iodide, a base such as TBAI(tetrabutylammonium iodide), K₂CO₃ (potassium carbonate) and a solventsuch as acetonitrile to obtain the compound 1f (wherein R⁵; R³ and p areas defined for compound 1a).

Step 1.5:

The compound 1f is treated with hydrogen, palladium catalyst in asolvent such as methanol to obtain compound 1g (wherein R⁵; R³ and p areas defined for compound 1a).

Step 1.6:

The compound 1g is treated with 0.4 equivalents of PBr₃ (Phosphorustribromide) at a temperature of 0° C. for 0.5 hours to obtain thecompound 1h (wherein R⁵, R³ and p are as defined for compound 1a).

Step 1.7:

Treatment of the compound 1h with triphenyiphosphine and toluene at atemperature of 60° C. for 2 hours resulted in compound of formula 1i, aWittig salt (wherein R⁵; R³ and pare as defined for compound 1a).

Step 1.8:

In this process step, the compound 1i is treated with a compound offormula 1j,

in the presence of NaOMe (Sodium methoxide) and a solvent such asmethanol for 1 hour to obtain compound 1k (wherein R⁴ and R⁵ arehydrogen or methyl; R¹, R², R³, m and p are as defined in any one of theembodiments of the compound of Formula I described herein).

Step 1.9:

The compound 1k is treated with Pd/C under hydrogen in a solvent such asmethanol to obtain compound 1l (wherein R⁴ and R⁵ are hydrogen ormethyl; R¹, R², R³, m and p are as defined in any one of the embodimentsof the compound of Formula I described herein).

Step 1.10:

The compound 1l is treated lithium hydroxide in a solvent mixture suchas THF:methanol (4:1) for 24 hours to obtain compound 1m (wherein R⁴ andR⁵ are hydrogen or methyl; R¹, R², R³, m and p are as defined in any oneof the embodiments of the compound of Formula I described herein).

Step 1.11:

The compound 1k is treated with lithium hydroxide in a solvent mixturesuch as THF:methanol (4:1) for 24 hours to obtain compound 1n (whereinR⁴ and R⁵ are hydrogen or methyl; R′, R², R³, m and p are as defined inany one of the embodiments of the compound of Formula I describedherein).

Step 1.12:

Preparation of compound of formula 1j: Suzuki coupling reaction ofsubstituted bromobenzaldehyde compound (1o) (wherein R² and n are asdefined in any one of the embodiments of the compound of Formula Idescribed herein) using tetrakis(triphenylphosphine)palladium(0), sodiumbicarbonate in water, in solvent dioxane, DMF (dimethylformamide)resulted in compound (1j) (wherein R¹, R², m and n are as defined in anyone of the embodiments of the compound of Formula I described herein).

Scheme 2:

Preparation of the compound of Formula I [referred in Scheme 2 as thecompound 2n (wherein R⁴ and R⁵ are hydrogen or methyl; R¹, R², R³, m andp are as defined in any one of the embodiments of the compound ofFormula I described herein)].

Step 2.1:

Suzuki coupling reaction of substituted bromobenzaldehyde compound (2a)(wherein R² and n are as defined in any one of the embodiments of thecompound of Formula I described herein) with a suitably substitutedboronic acid compound, using tetrakis(triphenylphosphine)palladium(0)resulted in compound (2b) (wherein R¹, R², m and n are as defined in anyone of the embodiments of the compound of Formula I described herein).

Step 2.2:

In this process step, the compound 2b is treated with dimethyl(1-diazo-2-oxopropyl)phosphonate or trimethylsilyldiazomethane, LDA(Lithium diisopropylamide) in the presence of a base selected from K₂CO₃or NaHCO₃ in THF and a solvent such as methanol to obtain an ethynylcompound (2c) (wherein R¹, R², m and n are as defined in any one of theembodiments of the compound of Formula I described herein).

Step 2.3:

In this process step, bromo compound of formula (2d) (wherein R³ and pare as defined in any one of the embodiments of the compound of FormulaI described herein) is subjected to Negishi Coupling with(4-ethoxy-4-oxobutyl)zinc(II) bromide compound (2e) in the presence ofPEPPSI-IPr catalyst[1,3-Bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)dichloride or Pd(0), under argon atmosphere in THF to obtain compound(2f) (wherein R³ and p are as defined in any one of the embodiments ofthe compound of Formula I described herein).

Step 2.4:

In this process step, the compound 2f is treated with Pd/C underhydrogen in ethanol to obtain the corresponding hydroxyl compound (2g)(wherein R³ and p are as defined in any one of the embodiments of thecompound of Formula I described herein).

Step 2.5:

The Compound 2g is reacted with triflic anhydride and pyridine under aninert atmosphere to obtain compound 2h (wherein R³ and p are as definedin any one of the embodiments of the compound of Formula I describedherein).

Step 2.6:

The ethynyl compound 2c obtained in the process step 2.2 was reactedwith the compound 2h, which is obtained in process step 2.5, in thepresence of copper(I) iodide, LiCl (Lithium chloride), TEA(Triethanolamine), Pd(PPh₃)₂Cl₂ (Bis(triphenylphosphine)palladium(II)dichloride) to obtain an ester compound 2i (wherein R⁵ is hydrogen ormethyl; R³ and p are as defined in any one of the embodiments of thecompound of Formula I described herein).

Step 2.7:

The compound 2i was hydrolyzed using LiOH.H₂O and a solvent THF:MeOH(4:1) for 24 hours to obtain the corresponding acid compound 2j (whereinR¹, R², R³, p, m and n are as defined in any one of the embodiments ofthe compound of Formula I described herein).

Step 2.8:

In this process step, the compound 2i was subjected to reduction usingLindlar catalyst and hydrogen to obtain compound 2k (wherein R⁴ and R⁵are hydrogen or methyl; R¹, R², R³, m and p are as defined in any one ofthe embodiments of the compound of Formula I described herein).

Step 2.9:

The compound 2k was hydrolyzed using LiOH.H₂O and a solvent mixture suchas THF:MeOH (4:1) for 24 hours to obtain compound of formula 2l (whereinR⁴ and R⁵ are hydrogen or methyl; R¹, R², R³, m and p are as defined inany one of the embodiments of the compound of Formula I describedherein).

Step 2.10:

In this process step, the compound 2k is treated with Pd/C underhydrogen in ethanol to obtain compound (2m) (wherein R⁴ and R⁵ arehydrogen or methyl; R¹, R², R³, m and p are as defined in any one of theembodiments of the compound of Formula I described herein).

Step 2.11:

The compound 2m is treated with lithium hydroxide and a solvent mixturesuch as THF:methanol (4:1) for 24 hours to obtain compound 2n (whereinR⁴ and R⁵ are hydrogen or methyl; R¹, R², R³, m and p are as defined inany one of the embodiments of the compound of Formula I describedherein).

Scheme 3:

Preparation of the compound of Formula I [referred to in Scheme 3 as thecompound 3g (wherein R¹, R², R³ and p are as defined in any one of theembodiments of the compound of Formula I described herein)].

Step 3.1:

Compound (3a) is reacted with the compound (3b) (wherein R³ and p are asdefined in any one of the embodiments of the compound of Formula Idescribed herein) with AlCl₃ (Aluminium chloride) to obtain compound(3c) (wherein R³ and p are as defined for the compound (3b)).

Step 3.2:

The compound (3c) obtained in step 3.1 is treated withethane-1,2-dithiol, boron trifluoride diethyl etherate and a solvent DCM(dichloromethane) at room temperature for overnight to obtain compound(3d) (wherein R³ and p are as defined for the compound (3b)).

Step 3.3:

The compound (3d) is treated with Olah's Reagent (hydrofluoricacid-pyridine solution), N-iodosuccinamide and a solvent such as DCM(dichloromethane) at −78° C. to obtain compound (3e) (wherein R³ and pare as defined for the compound (3b)).

Step 3.4:

Suzuki coupling reaction of compound (3e) (wherein R³ and p are asdefined in any one of the embodiments of the compound of Formula Idescribed herein) with the compound of formula 3f, usingtetrakis(triphenylphosphine)palladium(0), sodium bicarbonate in waterand solvent dioxane and DMF (Dimethylformamide) resulted in compound(3g) (wherein R¹, R³, m and p are as defined in any one of theembodiments of the compound of Formula I described herein).

Step 3.5:

The compound (3g) is hydrolysed with LiOH and a solvent mixture such asTHF:MeOH (4:1) for 6 hours to obtain the compound (3h) (wherein R¹, R³and p are as defined for the compound (3b)).

The compounds of formula (I) encompassed in the present invention asrecited in one or more embodiments as described above can be convertedinto their pharmaceutically acceptable salts by following procedureknown to persons skilled in the art.

The pharmaceutically acceptable salt of the compounds of Formula (I) areprepared with relatively non-toxic acids or bases, depending on theparticular substituents found on the compound described herein. When thecompounds of Formula (I) of the present invention contain an acidicgroup they can form an addition salt with a suitable base. For example,pharmaceutically acceptable base addition salts of the compounds of thepresent invention may include their alkali metal salts such as sodium,potassium, calcium, magnesium, ammonium or an organic base additionsalt. Examples of pharmaceutically acceptable organic base additionsalts of the compounds of the present invention include those derivedfrom organic bases like lysine, arginine, guanidine, diethanolamine,metformin or other organic bases known to the person skilled in the art.

When the compounds of Formula (I) of the present invention contain oneor more basic groups, they can form an addition salt with an inorganicor an organic acid. Examples of pharmaceutically acceptable acidaddition salts include those derived from inorganic acids like boricacid, perchloric acid, hydrochloric acid, hydrobromic acid, hydrofluoricacid, hydriodic acid, nitric acid, carbonic acid, monohydrogencarbonicacid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoricacid, sulfuric acid, monohydrogensulfuric acid, phosphorous acids orother inorganic acids known to the person skilled in the art.Furthermore, examples of pharmaceutically acceptable acid addition saltsinclude the salts derived from organic acids such as acetic acid,propionic acid, isobutyric acid, oxalic acid, malic acid, tartaric acid,citric acid, ascorbic acid, maleic acid, malonic acid, benzoic acid,succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid,benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid,glucuronic acid, galacturonic acid, naphthoic acid, camphoric acid orother organic acids known to the person skilled in the art. Certainspecific compounds of the present invention contain both basic andacidic functionalities that allow the compounds to be converted intoeither base or acid addition salts.

The pharmaceutically acceptable salts of the present invention can besynthesized from the subject compound i.e. the compound of Formula (I)which contains a basic or acidic moiety by conventional chemicalmethods. Generally, the salts are prepared by contacting the free baseor acid with an appropriate salt-forming inorganic or organic acid or abase in a suitable solvent or dispersant or by anion exchange or cationexchange with other salts. Suitable solvents are, for example, ethylacetate, ethers, alcohols, acetone, or mixtures of these solvents.

The compounds encompassed in the present invention can be regeneratedfrom their corresponding salts by contacting the said salt with anappropriate base or acid depending on the type of salt and isolating theparent compound 1n the conventional manner. The corresponding salts ofthe compounds differ from their parent compounds with respect to certainphysical properties, for example solubility.

In an embodiment of the present invention, the compound of Formula (I)or the compound of Formula (IA) or the compound of Formula (IB) or thecompound of Formula (IC) is provided as its correspondingpharmaceutically acceptable salt.

Those skilled in the art will recognize that the compounds of Formula(I) of the present invention contain asymmetric or chiral centres, andtherefore exist in different stereoisomeric forms, as racemic mixturesof enantiomers, mixtures of diastereomers or enantiomerically oroptically pure compounds. The term “chiral” refers to molecules whichhave the property of non-superimposability of the mirror image cohort,while the term “achiral” refers to molecules which are superimposable ontheir mirror image partner. It is intended that all stereoisomeric formsof the compounds of the invention, including but not limited to,diastereomers and enantiomers, as well as mixtures thereof such asracemic mixtures, geometric isomers form part of the present invention.

When the compounds of Formula (I) of the present invention contain onechiral centre, the compounds exist in two enantiomeric forms and thepresent invention includes both enantiomers and mixtures of enantiomers,such as the specific 50:50 mixture referred to as a racemic mixtures.The enantiomers can be resolved by methods known to those skilled in theart, such as formation of diastereoisomeric salts which may beseparated, for example, by crystallization (see, CRC Handbook of OpticalResolutions via Diastereomeric Salt Formation by David Kozma (CRC Press,2001)); formation of diastereoisomeric derivatives or complexes whichmay be separated, for example, by crystallization, gas-liquid or liquidchromatography; selective reaction of one enantiomer with anenantiomer-specific reagent, for example enzymatic esterification; orgas-liquid or liquid chromatography in a chiral environment, for exampleon a chiral support for example silica with a bound chiral ligand or inthe presence of a chiral solvent. It will be appreciated that where thedesired enantiomer is converted into another chemical entity by one ofthe separation procedures described above, a further step is required toliberate the desired enantiomeric form. Alternatively, specificenantiomers can be synthesized by asymmetric synthesis using opticallyactive reagents, substrates, catalysts or solvents, or by converting oneenantiomer into the other by asymmetric transformation. Designation of aspecific absolute configuration at a chiral carbon of the compounds ofthe invention is understood to mean that the designated enantiomericform of the compounds is in enantiomeric excess (ee) or in other wordsis substantially free from the other enantiomer. For example, the “R”forms of the compounds are substantially free from the “S” forms of thecompounds and are, thus, in enantiomeric excess of the “S” forms.Conversely, “S” forms of the compounds are substantially free of “R”forms of the compounds and are, thus, in enantiomeric excess of the “R”forms. Enantiomeric excess, as used herein, is the presence of aparticular enantiomer at greater than 50%. In a particular embodimentwhen a specific absolute configuration is designated, the enantiomericexcess of depicted compounds is at least about 90%. When a compound ofFormula (I) of the present invention has two or more chiral carbons itcan have more than two optical isomers and can exist indiastereoisomeric forms. For example, when there are two chiral carbons,the compound can have up to 4 optical isomers and 2 pairs of enantiomers((S,S)/(R,R) and (R,S)/(S,R)). The pairs of enantiomers (e.g.,(S,S)/(R,R)) are mirror image stereoisomers of one another. Thestereoisomers that are not mirror-images (e.g., (S,S) and (R,S)) arediastereomers. The diastereoisomeric pairs may be separated by methodsknown to those skilled in the art, for example chromatography orcrystallization and the individual enantiomers within each pair may beseparated as described above. The present invention includes eachdiastereoisomer of such compounds and mixtures thereof.

In one embodiment, the compounds of Formula (I) exist as tautomers, andit is intended to encompass all the tautomeric forms of the compoundswithin the scope of the present invention.

The present invention furthermore includes all the solvates of thecompounds of Formula (I), for example, hydrates and the solvates formedwith other solvents of crystallisation, selected from alcohols such asmethanol, ethanol, 1-propanol or 2-propanol, ethers such as diethylether, isopropyl ether or tetrahydrofuran, esters such as methyl acetateor ethyl acetate, ketone such as acetone or their mixtures thereof.Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms.

It is further intended to encompass various polymorphs of the compoundsof Formula (I) within the scope of the present invention. Variouspolymorphs of the compounds of the present invention can be prepared bystandard crystallisation procedures known in the art. Thecrystallisation technique employed can utilize various solvents or theirmixtures, temperature conditions and various modes of cooling, rangingfrom very fast to very slow cooling. The presence of polymorphs can bedetermined by IR (Infra-red) spectroscopy, solid probe NMR (NuclearMagnetic Resonance) spectroscopy, differential scanning calorimetry,powder X-ray diffraction or such other standard techniques.

Furthermore, the present invention also includes prodrugs of thecompounds of Formula (I). The prodrugs of the compounds of the presentinvention are derivatives of the aforesaid compounds of the inventionwhich upon administration to a subject in need thereof undergoeschemical conversion by metabolic or chemical processes to release theparent drug in vivo from which the prodrug is derived. The preferredprodrugs are pharmaceutically acceptable ester derivatives e.g., alkylesters, cycloalkyl esters, alkenyl esters, benzyl esters, mono- ordi-substituted alkyl esters convertible by solvolysis underphysiological conditions to the parent carboxylic acid, and thoseconventionally used in the art.

The present invention further relates to carboxylic acid isosteres ofthe compounds of Formula (I).

The present invention also relates to N-oxide derivatives of thecompounds of Formula (I).

The present invention also relates to S-oxide derivatives of thecompounds of Formula (I).

In one aspect of the present invention, the compounds of Formula (I) areGPR120 agonists.

In an embodiment of the present invention, the compounds of Formula (I)find use in the treatment or prophylaxis of a disease or a disordermediated by GPR120.

In another aspect, the present invention relates to a method for thetreatment or prophylaxis of a disease or a disorder mediated by GPR120,comprising administering to a subject in need thereof, a therapeuticallyeffective amount of a compound of Formula (I) or a stereoisomer, atautomer or a pharmaceutically acceptable salt thereof.

In an embodiment, the present invention relates to use of the compoundof Formula (I) or a stereoisomer, a tautomer or a pharmaceuticallyacceptable salt thereof; for the treatment or prophylaxis of a diseaseor a disorder mediated by GPR120.

According to one embodiment, the present invention relates to use of thecompounds of Formula (I) or a stereoisomer, a tautomer or apharmaceutically acceptable salt thereof; in the manufacture of amedicament for the treatment or prophylaxis of a disease or a disordermediated by GPR120.

In an embodiment of the invention, the disease or disorder mediated byGPR120 is selected from the group consisting of diabetes, obesity,hyperglycemia, glucose intolerance, insulin resistance,hyperinsulinemia, hypercholesterolemia, hypertension,hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia,dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease,atherosclerosis, kidney disease, polycystic ovary syndrome,ketoacidosis, thrombotic disorders, diabetic nephropathy, diabeticneuropathy, diabetic retinopathy, sexual dysfunction, fatty liverdevelopment, dermatopathy, dyspepsia, hypoglycemia, cancer, edema,pancreatic beta cell degeneration, and a disorder associated withpancreatic beta cell degeneration.

In an embodiment of the invention, the disease or disorder mediated byGPR120 is selected from the group consisting of diabetes, obesity,insulin resistance, hyperglycemia, glucose intolerance,hypercholesterolemia, hypertriglylceridemia, dyslipidemia,hyperlipoproteinemia, hyperinsulinemia, atherosclerosis, diabeticnephropathy, diabetic neuropathy, diabetic retinopathy, metabolicsyndrome, syndrome X, hypertension and pancreatic beta celldegeneration.

In an embodiment of the invention, the disease or disorder mediated byGPR120 is selected from the group consisting of diabetes, obesity,insulin resistance, hyperglycemia, glucose intolerance, metabolicsyndrome, syndrome X and pancreatic beta cell degeneration.

In an embodiment, diabetes is Type 2 diabetes.

In an embodiment, the disease or disorder mediated by GPR120 is ametabolic disorder which refers to one or more diseases or disorders asidentified above.

In an embodiment, the disease or disorder mediated by GPR120 is aninflammatory disorder.

Accordingly, the present invention relates to a method for the treatmentor prophylaxis of a metabolic disorder, comprising administering to asubject in need thereof a therapeutically amount of a compound ofFormula (I) or a stereoisomer, a tautomer or a pharmaceuticallyacceptable salt thereof.

In an embodiment, the present invention provides use of the compound ofFormula (I) or a stereoisomer, a tautomer or a pharmaceuticallyacceptable salt thereof; for the treatment or prophylaxis of a metabolicdisorder.

According to one embodiment, the present invention relates to use of thecompound of Formula (I) or a pharmaceutically acceptable salt thereof inthe manufacture of a medicament, for the treatment or prophylaxis of ametabolic disorder.

In one embodiment, the metabolic disorder is selected from the groupconsisting of diabetes, obesity, cardiovascular disease, hypertension,ketoacidosis, insulin resistance, glucose intolerance, hyperglycemia,hypertriglylceridemia, polycystic ovary syndrome, hypercholesterolemia,hyperlipoproteinemia, dyslipidemia, metabolic syndrome, syndrome X,hyperlipidemia, diabetic nephropathy, diabetic neuropathy, diabeticretinopathy, edema and related disorders associated with abnormal plasmalipoprotein, triglycerides, pancreatic beta cell degeneration; and adisorder associated with pancreatic beta cell degeneration.

In an embodiment, the metabolic disorder is selected from the groupconsisting of diabetes, obesity, insulin resistance, hyperglycemia,glucose intolerance, hypercholesterolemia, hypertriglylceridemia,dyslipidemia, hyperlipoproteinemia, hyperinsulinemia, atherosclerosis,diabetic nephropathy, diabetic neuropathy, diabetic retinopathy,metabolic syndrome, syndrome X, hypertension and pancreatic beta celldegeneration.

In an embodiment, the metabolic disorder is selected from the groupconsisting of diabetes, obesity, insulin resistance, glucoseintolerance, dyslipidemia, hyperinsulinemia, syndrome X, metabolicsyndrome and pancreatic beta cell degeneration.

In an embodiment, the metabolic disorder is Type 2 diabetes.

The present invention furthermore relates to pharmaceutical compositionsthat contain a therapeutically effective amount of at least one compoundof Formula (I) or its pharmaceutically acceptable salt in addition to acustomary pharmaceutically acceptable carrier, and to a process for theproduction of a pharmaceutical composition, which includes bringing atleast one compound of Formula (I), into a suitable administration formusing a pharmaceutically suitable and physiologically tolerableexcipient and, if appropriate, further additives or auxiliaries.

According to one embodiment, the present invention relates to apharmaceutical composition comprising the compound of Formula (I) or apharmaceutically acceptable salt thereof; and one or morepharmaceutically acceptable excipients; for use in the treatment orprophylaxis of a disease or a disorder mediated by GPR120.

It is further intended to include within the scope of the presentinvention the use of the compounds of Formula (I) or itspharmaceutically acceptable salts thereof in combination with at leastone further therapeutically active agent.

According to one embodiment, the present invention provides apharmaceutical composition, comprising a therapeutically effectiveamount of a compound of Formula (I) or a pharmaceutically acceptablesalt thereof; and at least one further therapeutically active agent,together with a pharmaceutically acceptable excipient.

In an embodiment, the present invention relates to use of the compoundof Formula (I) or a pharmaceutically acceptable salt thereof; incombination with a further therapeutically active compound, in thetreatment or prophylaxis of a disease or a disorder mediated by GPR120.

The therapeutically active agent used in combination with one or more ofthe compounds of Formula (I) can be selected from the compounds ortherapeutically active substances known to be used in the treatment ofdiabetes and other conditions/disorders such as obesity, insulinresistance, hyperglycemia, glucose intolerance, hypercholesterolemia,hypertriglylceridemia, dyslipidemia, hyperlipoproteinemia,hyperinsulinemia or atherosclerosis. According to the present invention,the therapeutically active agent, used in combination with the compoundsof Formula (I) of the present invention can be selected from, but notlimited to, insulin, sulfonylureas, biguanidines, meglitinides,oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors,inhibitors of glycogen phosphorylase, glucagon antagonists, HMGCoAreductase inhibitor, GLP-1 (Glucogen-like peptide-1) agonists, potassiumchannel openers, inhibitors of dipeptidylpeptidase IV (DPP-IV),diglyceride acyltransferase (DGAT) inhibitor, insulin sensitizers,modulators of glucose uptake, modulators of glucose transport andmodulators of glucose reabsorption, modulators of the sodium-dependentglucose transporter 1 or 2 (SGLT1, SGLT2), compounds which alter lipidmetabolism such as antihyperlipidemic active ingredients andantilipidemic active ingredients, PPARgamma agonists and agents withcombined PPARalpha and gamma activity and active ingredients which acton the ATP-dependent potassium channel of the beta cells.

In an embodiment, the compound of Formula (I) can be used in combinationwith a PPAR gamma agonist selected from rosiglitazone, pioglitazone,rivoglitazone, and the like.

In an embodiment, the compound of Formula (I) can be used in combinationwith a HMGCoA reductase inhibitor selected from simvastatin,fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin,rosuvastatin, and the like.

In an embodiment, the compound of Formula (I) can be used in combinationwith a sulfonylurea selected from tolbutamide, glibenclamide, glipizide,glimepiride, and the like.

In another embodiment, the compound of the Formula (I) can be used incombination with a meglitinide selected from repaglinide, nateglinide,mitiglinide, and the like.

In another embodiment, the compound of the Formula (I) can be used incombination with GLP-1 agonist selected from exenatide, liraglutide,taspoglutide albiglutide, lixisenatide, and the like.

In another embodiment, the compound of the Formula (I) can be used incombination with DPP-IV inhibitor selected from alogliptin, gemigliptin,linagliptin, saxagliptin, sitagliptin, vildagliptin, and the like.

Accordingly, in an embodiment the further therapeutically active agentthat can be used in combination with one or more compounds of Formula(I) encompassed in the present invention, can be selected from one ormore of the agents including, but not limited to, insulin,rosiglitazone, pioglitazone, rivoglitazone, simvastatin, fluvastatin,pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin,tolbutamide, glibenclamide, glipizide, glimepiride, repaglinide,nateglinide, mitiglinide, exenatide, liraglutide, taspoglutidealbiglutide, lixisenatide, alogliptin, gemigliptin, linagliptin,saxagliptin, sitagliptin, vildagliptin, and the like.

The pharmaceutical compositions according to the present invention areprepared in a manner known and familiar to one skilled in the art.Pharmaceutically acceptable inert inorganic and/or organic carriersand/or additives can be used in addition to the compound of Formula (I)and/or its pharmaceutically acceptable salts. For the production ofpills, tablets, coated tablets and hard gelatin capsules it is possibleto use, for example, lactose, corn starch or derivatives thereof, gumarabic, magnesia or glucose, etc. Carriers for soft gelatin capsules andsuppositories are, for example, fats, waxes, natural or hardened oils,etc. Suitable carriers for the production of solutions, for exampleinjection solutions, or of emulsions or syrups are, for example, water,physiological sodium chloride solution or alcohols, for example,ethanol, propanol or glycerol, sugar solutions, such as glucosesolutions or mannitol solutions, or a mixture of the various solventswhich have been mentioned.

Further, the pharmaceutical composition of the present invention canalso contain additives such as fillers, antioxidants, emulsifiers,preservatives, flavours, solubilisers or colourants. The pharmaceuticalcomposition of the present invention may also contain two or morecompounds of Formula (I) and/or its pharmaceutically acceptable salts,the pharmaceutical compositions can also contain one or more othertherapeutically or prophylactically active ingredients.

The pharmaceutical compositions normally contain about 1 to 99%, forexample, about 10 to 80%, by weight of the compounds of Formula (I) ortheir pharmaceutically acceptable salts.

The amount of the active ingredient i.e. the compound of Formula (I) orits pharmaceutically acceptable salt in the pharmaceutical compositionscan, for example, vary from about 1 to 500 mg. In case of higher bodyweight of the mammal in need of the treatment, the pharmaceuticalcomposition may contain the compound of Formula (I) or itspharmaceutically acceptable salt in an amount ranging from 5 mg to 1000mg. The desirable dosage of the compounds of Formula (I) or itspharmaceutically acceptable salt can be selected over a wide range. Thedaily dosage to be administered is selected to achieve the desiredtherapeutic effect in subjects being treated for metabolic disorders. Adosage of about 0.05 to 50 mg/kg/day of the compounds of Formula (I) orits pharmaceutically acceptable salt may be administered. In case ofhigher body weight of the mammal in need of the treatment, a dosage ofabout 0.1 to 100 mg/kg/day of the compound of Formula (I) or itspharmaceutically acceptable salt may be administered. If required,higher or lower daily dosages can also be administered. Actual dosagelevels of the active ingredients in the pharmaceutical composition ofthis present invention can be varied so as to obtain an amount of theactive ingredient, which is effective to achieve the desired therapeuticresponse for a particular patient (subject), composition, and mode ofadministration without being toxic to the patient. The selected dosagelevel can be readily determined by a skilled medical practitioner in thelight of the relevant circumstances, including the condition (diseasesor disorder) to be treated, the chosen route of administration dependingon a number of factors, such as age, weight and physical health andresponse of the individual patient, pharmacokinetics, severity of thedisease and the like, factors known in the medical art.

The pharmaceutical compositions according to the present invention canbe administered orally, for example in the form of pills, tablets,coated tablets, capsules, granules or elixirs. Administration, however,can also be carried out rectally, for example in the form ofsuppositories, or parenterally, for example intravenously,intramuscularly or subcutaneously, in the form of injectable sterilesolutions or suspensions, or topically, for example in the form ofsolutions or transdermal patches, or in other ways, for example in theform of aerosols or nasal sprays.

It is understood that modifications that do not substantially affect theactivity of the various embodiments of this invention are includedwithin scope of the invention disclosed herein. Accordingly, thefollowing examples are intended to illustrate but not to limit scope ofthe present invention.

EXPERIMENTAL

Nomenclature of the compounds exemplified in the present invention wasderived from Chemdraw Ultra version 9.0.1 CambridgeSoft Corporation,Cambridge.

Reagents were purchased from commercial suppliers such as Combi-BlocksInc., CA; and CombiPhos Catalysts, Inc; and were used as such.

Unless otherwise stated all temperatures are in degree celsius. Also, inthese examples and elsewhere, abbreviations have the following meanings:

The abbreviations and terms that are used herein:

LIST OF ABBREVIATIONS Pd/C Palladium on carbon mmole Millimoles CDCl₃Deuterated chloroform mL Millilitre ° C. Degree celcius nM Nanomolar DMFN,N-dimethyl formamide DMSO-d₆ Deuterated dimethylsulfoxide DMSODimethyl sulfoxide DCM Dichloromethane g gram μM Micromolar LiOH•H₂OLithium hydroxide Pd(PPh₃)₂Cl₂ Bis(triphenylphosphine) monohydratepalladium(II) dichloride mg milligram RT Room temperature MeOH MethanolPET Petroleum ether mM Millimolar THF Tetrahydrofuran PEPPSI-IPr[1,3-Bis(2,6-diisopropylphenyl)imidazol-2- catalystylidene](3-chloropyridyl) palladium(II) dichloride

Example 14-(5-((5-Fluoro-2-(6-methoxypyridin-3-yl)phenyl)ethynyl)pyridin-2-yl)butanoicacid (Compound 1) Step 1a Synthesis of 5-(benzyloxy)-2-bromopyridine

To 6-bromopyridin-3-ol (10 g, 57.5 mmol) and cesium carbonate (28.1 g,86 mmol) in acetonitrile (50 mL), benzyl bromide (8.20 mL, 69.0 mmol)was added and the reaction mass was allowed to stir at room temperatureovernight. The reaction mass was quenched with water and extracted withethyl acetate (2×100 mL), organic layer was dried over sodium sulphateand concentrated to give crude mass which was purified using columnchromatography to provide 5-(benzyloxy)-2-bromopyridine (12.3 g, 46.1mmol, 80% yield).

¹H NMR (300 MHz, CDCl₃): δ 8.19 (d, J=1.5 Hz, 1H), 7.55 (d, J=8.7 Hz,1H), 7.47-7.32 (m, 6H), 5.18 (s, 2H); LCMS (m/z): 265 (M+1).

Step 1b Synthesis of ethyl 4-(5-(benzyloxy)pyridin-2-yl)butanoate

5-(Benzyloxy)-2-bromopyridine (6 g, 22.72 mmol) was stirred in dry THF(20 mL) under argon atmosphere. (4-Ethoxy-4-oxobutyl)zinc(II) bromide(50.0 mL, 24.99 mmol) in THF was added carefully under argon atmospherefollowed by[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)dichloride (Peppsi catalyst) (0.772 g, 1.136 mmol) and reaction stirredat room temperature overnight. Reaction mixture was quenched withsaturated solution of ammonium chloride and extracted with ethyl acetate(2×25 mL). Organic layer was washed with brine (25 mL), dried andconcentrated to obtain crude which was purified using columnchromatography to provide ethyl 4-(5-(benzyloxy)pyridin-2-yl)butanoate.(4.3 g, 14.23 mmol, 62.6% yield).

¹H NMR (300 MHz, CDCl₃): δ 8.25 (d, J=3.0 Hz, 1H), 7.46-7.31 (m, 6H),7.16 (d, J=8.4 Hz, 1H), 5.14 (s, 2H), 4.03 (q, J=6.9 Hz, 2H), 2.82 (t,J=7.2 Hz, 2H), 2.66 (t, J=7.2 Hz, 2H), 1.93-1.83 (m, 2H), 1.19 (t, J=6.9Hz, 3H); LCMS (m/z): 300.1 (M+1).

Step 1c Synthesis of ethyl 4-(5-hydroxypyridin-2-yl)butanoate

To a solution of ethyl 4-(5-(benzyloxy)pyridin-2-yl)butanoate (4.2 g,14.03 mmol) in ethanol (25 mL), Pd/C (0.149 g, 1.403 mmol) was added andthe flask was shaken under hydrogen atmosphere at 40 psi for 4 hours.After completion of the reaction, it was filtered through celite andconcentrated to provide ethyl 4-(5-hydroxypyridin-2-yl)butanoate. (2.7g, 12.79 mmol, 91% yield).

¹H NMR (300 MHz, CDCl₃): δ 9.7 (s, 1H), 8.02 (d, J=2.1 Hz, 1H),7.08-7.01 (m, 2H), 4.03 (q, J=6.0 Hz, 2H), 2.61 (t, J=7.5 Hz, 2H), 2.27(t, J=7.5 Hz, 2H), 1.90-1.30 (m, 2H), 1.19 (t, J=6.9 Hz, 3H); MS (m/z):210.1 (M+1).

Step 1d Synthesis of ethyl4-(5-(((trifluoromethyl)sulfonyl)oxy)pyridin-2-yl)butanoate

To a solution of ethyl 4-(5-hydroxypyridin-2-yl)butanoate (250 mg, 1.195mmol) in DCM (10 mL) was added pyridine (0.773 mL, 9.56 mmol), triflicanhydride (0.505 mL, 2.99 mmol) under nitrogen atmosphere and allowed tostir overnight. After completion of reaction, the reaction mass wasconcentrated and purified using column chromatography to provide ethyl4-(5-(((trifluoromethyl)sulfonyl)oxy)pyridin-2-yl)butanoate. (0.315 g,0.917 mmol, 77% yield).

¹H NMR (300 MHz, CDCl₃): δ 8.68 (d, J=2.7 Hz, 1H), 7.95 (dd, J=3.0 Hz,J=5.7 Hz, 1H), 7.48 (d, J=7.2 Hz, 1H), 4.07 (q, J=7.2 Hz, 2H), 2.82 (t,J=5.7 Hz, 2H), 2.33 (t, J=7.5 Hz, 2H), 1.93 (m, 2H), 1.71 (t, J=6.9 Hz,3H); MS (m/z): 342.1 (M+1).

Step 1e Synthesis of 5-fluoro-2-(6-methoxypyridin-3-yl)benzaldehyde

2-Bromo-5-fluorobenzaldehyde (2 g, 9.85 mmol) was added to a stirredsolution of (6-methoxypyridin-3-yl)boronic acid (1.808 g, 11.82 mmol),sodium bicarbonate (1.655 g, 19.70 mmol) in 1,4-dioxane:water (16 mL:4mL). The reaction mass was degassed and flushed with nitrogen,tetrakis(triphenylphosphine)palladium(0) (1.138 g, 0.985 mmol) was thenadded. It was flushed with nitrogen and stirred at 111° C. for 3 hours.Reaction mixture was cooled, diluted with water and extracted with ethylacetate (2×25 mL). Ethyl acetate layer was washed with brine (25 mL),dried over sodium sulphate and concentrated to get crude. The crudeobtained was purified by column chromatography to provide5-fluoro-2-(6-methoxypyridin-3-yl)benzaldehyde. (1.7 g, 7.35 mmol, 74.6%yield).

¹H NMR (300 MHz, CDCl₃): δ 9.85 (d, J=3.0 Hz, 1H), 8.23 (d, J=2.1 Hz,1H), 7.84 (dd, J=2.4 Hz, J=6.3 Hz, 1H), 7.69-7.57 (m, 3H), 6.95 (d,J=8.4 Hz, 1H), 3.92 (s, 3H); MS (m/z): 232.1 (M+1).

Step 1f Synthesis of 5-(2-ethynyl-4-fluorophenyl)-2-methoxypyridine

Dimethyl (1-diazo-2-oxopropyl)phosphonate (1.246 mL, 0.519 mmol) wasadded dropwise to a solution of5-fluoro-2-(6-methoxypyridin-3-yl)benzaldehyde (100 mg, 0.432 mmol) andpotassium carbonate (120 mg, 0.865 mmol) in dry methanol (5 mL) at roomtemperature under argon, and the mixture was stirred at room temperaturefor 15 minutes. The reaction was quenched with brine (15 mL), and themixture was extracted with ethyl acetate (2×25 mL). The combined organiclayer was washed with brine (30 mL), dried over Na₂SO₄. Solvent wasremoved under reduced pressure and the crude obtained was purified bycolumn chromatography to provide5-(2-ethynyl-4-fluorophenyl)-2-methoxypyridine. (0.071 g, 0.309 mmol,75.1% yield).

¹H NMR (300 MHz, CDCl₃): δ 8.31 (d, J=2.1 Hz, 1H), 7.88 (dd, J=2.4 Hz,J=6.0 Hz, 1H), 7.51-7.46 (m, 2H), 7.40-7.57 (m, 1H), 6.90 (d, J=8.7 Hz,1H), 4.33 (s, 1H), 3.90 (s, 3H); MS (m/z): 228.0 (M+1).

Step 1g Synthesis of ethyl4-(5-((5-fluoro-2-(6-methoxypyridin-3-yl)phenyl)ethynyl)pyridin-2-yl)butanoate

To a solution of ethyl4-(5-(((trifluoromethyl)sulfonyl)oxy)pyridin-2-yl)butanoate (50 mg,0.146 mmol), 5-(2-ethynyl-4-fluorophenyl)-2-methoxypyridine (56.6 mg,0.249 mmol), lithium chloride (9.32 mg, 0.220 mmol), copper (I) iodide(1.395 mg, 7.32 μmol), triethanolamine (0.306 mL, 2.197 mmol) in DMF (2mL) was added bis(triphenylphosphine)palladium(II) chloride (2.057 mg,2.93 μmol) under nitrogen atmosphere. The reaction vessel was degassed,flushed with nitrogen and heated at 60° C. overnight. The reaction masswas distilled off and the crude was purified using column chromatographyto provide ethyl4-(5-((5-fluoro-2-(6-methoxypyridin-3-yl)phenyl)ethynyl)pyridin-2-yl)butanoate.(0.053 g, 0.124 mmol, 84% yield).

¹H NMR (300 MHz, CDCl₃): δ 8.52 (s, 1H), 8.36 (d, J=2.1 Hz, 1H), 7.88(dd, J=2.4 Hz, J=6.3 Hz, 1H), 7.57 (dd, J=1.8 Hz, J=6.0 Hz, 1H),7.39-7.35 (m, 2H), 7.19-7.12 (m, 2H), 6.85 (d, J=8.4 Hz, 1H), 4.14 (q,J=7.2 Hz, 2H), 4.01 (s, 3H), 2.85 (t, J=7.5 Hz, 2H), 2.36 (t, J=7.5 Hz,2H), 2.12-2.02 (m, 2H), 1.27 (t, J=7.2 Hz, 3H); MS (m/z): 419.1 (M+1).

Step 1h Synthesis of4-(5-((5-fluoro-2-(6-methoxypyridin-3-yl)phenyl)ethynyl)pyridin-2-yl)butanoicacid

To a solution of ethyl4-(5-((5-fluoro-2-(6-methoxypyridin-3-yl)phenyl)ethynyl)pyridin-2-yl)butanoate(50 mg, 0.119 mmol) in THF (4 mL), methanol (1.0 mL) was added LiOH(17.17 mg, 0.717 mmol) and allowed to stir at RT overnight. The reactionmass was distilled under vacuum, quenched with water (25 mL) and brine(25 mL) and extracted with ethyl acetate (2×25 mL). Combined organiclayer was dried over sodium sulphate and concentrated to provide4-(5-((5-fluoro-2-(6-methoxypyridin-3-yl)phenyl)ethynyl)pyridin-2-yl)butanoicacid. (0.032 g, 0.082 mmol, 68.5% yield).

¹H NMR (300 MHz, CDCl₃): δ 12.09 (s, 1H), 8.48 (s, 1H), 8.37 (d, J=2.1Hz, 1H), 8.03 (dd, J=2.4 Hz, J=6.3 Hz, 1H), 7.70 (dd, J=2.1 Hz, J=6.0Hz, 1H), 7.59-7.54 (m, 2H), 7.43-7.38 (m, 1H), 7.31 (d, J=8.1 Hz, 1H),6.96 (d, J=6.7 Hz, 1H), 3.91 (s, 3H), 2.76 (t, J=7.5 Hz, 2H), 2.23 (t,J=7.5 Hz, 2H), 1.90-1.88 (m, 2H); MS (m/z): 391.1 (M+1).

Example 24-(5-(5-Fluoro-2-(6-methoxypyridin-3-yl)phenethyl)pyridin-2-yl)butanoicacid (Compound 2) Step 2a Synthesis of ethyl4-(5-(5-fluoro-2-(6-methoxypyridin-3-yl)phenethyl)pyridin-2-yl)butanoate

To a solution of ethyl4-(5-((5-fluoro-2-(6-methoxypyridin-3-yl)phenyl)ethynyl)pyridin-2-yl)butanoate(70 mg, 0.167 mmol) in ethanol (25 mL), Pd/C (1.780 mg, 0.017 mmol) wasadded and the flask was stirred under hydrogen atmosphere at RTovernight. After completion of reaction, reaction mixture was filteredthrough celite and concentrated to provide ethyl4-(5-(5-fluoro-2-(6-methoxypyridin-3-yl)phenethyl)pyridin-2-yl)butanoate.(0.060 g, 0.137 mmol, 82% yield).

¹H NMR (300 MHz, CDCl₃): δ 8.08 (s, 1H), 8.01 (d, J=1.8 Hz, 1H), 7.59(dd, J=2.4 Hz, J=6.3 Hz, 1H), 7.30-7.06 (m, 5H), 6.86 (d, J=9.0 Hz, 1H),4.02 (q, J=9.0 Hz, 2H), 3.89 (s, 3H), 2.86-2.61 (m, 6H), 2.28 (t, J=6.0Hz, 2H), 1.91-1.82 (m, 2H), 1.16 (t, J=6.0 Hz, 3H); MS (m/z): 423.1(M+1).

Step 2b Synthesis of4-(5-(5-fluoro-2-(6-methoxypyridin-3-yl)phenethyl)pyridin-2-yl)butanoicacid

The title compound was prepared in an analogous manner as the compoundof Step 1h of Example 1, by using ethyl4-(5-(5-fluoro-2-(6-methoxypyridin-3-yl)phenethyl)pyridin-2-yl)butanoate(50 mg, 0.118 mmol) instead of ethyl4-(5-((5-fluoro-2-(6-methoxypyridin-3-yl)phenyl)ethynyl)pyridin-2-yl)butanoateto obtain4-(5-(5-fluoro-2-(6-methoxypyridin-3-yl)phenethyl)pyridin-2-yl)butanoicacid. (0.015 g, 0.036 mmol, 30.2% yield).

¹H NMR (CDCl₃, 300 MHz): δ 8.16 (s, 1H), 7.96 (s, 1H), 7.42 (dd, J=2.4Hz, J=6.0 Hz, 1H), 7.25 (s, 1H), 7.17-7.09 (m, 2H), 7.01 (d, J=6.0 Hz,2H), 6.80 (s, 1H), 3.99 (s, 3H), 2.95-2.73 (m, 6H), 2.40 (t, J=6.0 Hz,2H), 2.07 (t, J=6.0 Hz, 2H), 1.26 (t, J=3.0 Hz, 2H); MS (m/z): 395.2(M+1).

Example 34-(5-((5-Fluoro-2-(5-methylthiophen-2-yl)phenyl)ethynyl)pyridin-2-yl)butanoicacid (Compound 3) Step 3a Synthesis of5-fluoro-2-(5-methylthiophen-2-yl)benzaldehyde

2-Bromo-5-fluorobenzaldehyde (1 g, 4.93 mmol) was added to a stirredsolution of4,4,5,5-tetramethyl-2-(5-methylthiophen-2-yl)-1,3,2-dioxaborolane (1.987g, 8.87 mmol) and sodium bicarbonate (0.828 g, 9.85 mmol) in 20 mL of1,4-Dioxane:water (4:1). The reaction mass was degassed and flushed withnitrogen. Tetrakis(triphenylphosphine)palladium(0) (0.569 g, 0.493 mmol)was added to it and stirred at 111° C. for 3 hours. Reaction mixture wascooled, diluted with water and extracted with ethyl acetate (2×25 mL).The organic layer was washed with water (25 mL), brine (25 mL) and driedover sodium sulphate to obtain crude which was purified by columnchromatography to provide5-fluoro-2-(5-methylthiophen-2-yl)benzaldehyde. (0.650 g; 2.82 mmol,57.2% yield).

¹H NMR (300 MHz, CDCl₃): δ 10.04 (d, J=3.3 Hz, 1H), 7.66-7.57 (m, 3H),7.05 (d, J=3.3 Hz, 1H), 6.91 (d, J=2.4 Hz, 1H), 2.51 (s, 3H); MS (m/z):221 (M+1).

Step 3b Synthesis of 2-(2-ethynyl-4-fluorophenyl)-5-methylthiophene

Dimethyl (1-diazo-2-oxopropyl)phosphonate (2.62 mL, 1.090 mmol) wasadded dropwise to a solution of5-fluoro-2-(5-methylthiophen-2-yl)benzaldehyde (200 mg, 0.908 mmol) andpotassium carbonate (251 mg, 1.816 mmol) in dry methanol (2 mL) at RTunder argon, and the mixture was stirred at room temperature for 15minutes. The reaction was quenched with brine (15 mL), and the mixtureextracted with ethyl acetate (2×25 mL). The combined organic layer waswashed with brine (30 mL), dried over Na₂SO₄. Solvent was removed underreduced pressure and crude residue was purified by column chromatographyto provide 2-(2-ethynyl-4-fluorophenyl)-5-methylthiophene. (0.143 g,0.658 mmol, 72.5% yield).

¹H NMR (CDCl₃, 300 MHz): δ 7.58-7.54 (m, 1H), 7.42 (dd, J=6.6 Hz, J=2.7Hz, 1H), 7.31-7.27 (m, 2H), 6.83 (d, J=2.7 Hz, 1H), 4.52 (s, 1H), 2.51(s, 3H); MS (m/z): 217 (M+1).

Step 3c Synthesis of ethyl4-(5-((5-fluoro-2-(5-methylthiophen-2-yl)phenyl)ethynyl)pyridin-2-yl)butanoate

To a solution of ethyl4-(5-(((trifluoromethyl)sulfonyl)oxy)pyridin-2-yl)butanoate (50 mg,0.146 mmol), 2-(2-ethynyl-4-fluorophenyl)-5-methylthiophene (53.9 mg,0.249 mmol), lithium chloride (9.32 mg, 0.220 mmol), copper(I) iodide(1.395 mg, 7.32 μmol), triethylamine (0.306 mL, 2.197 mmol) indimethylformamide (2 mL), bis(triphenylphosphine)palladium(II) chloride(2.057 mg, 2.93 μmol) was added under nitrogen atmosphere. The reactionvessel was degassed and flushed with nitrogen and heated at 60° C.overnight. The reaction mass was distilled off and the crude waspurified using column chromatography to provide ethyl4-(5-((5-fluoro-2-(5-methylthiophen-2-yl)phenyl)ethynyl)pyridin-2-yl)butanoate.(0.055 g, 0.131 mmol, 89.0% yield).

¹H NMR (300 MHz, CDCl₃): δ 8.66 (s, 1H), 8.04 (s, 1H), 7.70 (dd, J=6.0Hz, J=2.1 Hz, 1H), 7.51 (q, J=5.7 Hz, 1H), 7.33 (d, J=3.9 Hz, 1H), 7.18(d, J=8.1 Hz, 1H), 7.12-7.05 (m, 1H), 6.78 (d, J=3.6 Hz, 1H), 4.15 (q,J=7.2 Hz, 2H), 2.86 (d, J=7.8 Hz, 2H), 2.55 (s, 3H), 2.39 (t, J=7.5 Hz,2H), 2.15-2.05 (m, 2H), 1.28 (t, J=7.2 Hz, 3H); HPLC (%): 96.81%; MS(m/z): 408.1 (M+1).

Step 3d Synthesis of4-(5-((5-fluoro-2-(5-methylthiophen-2-yl)phenyl)ethynyl)pyridin-2-yl)butanoicacid

To a solution of ethyl4-(5-((5-fluoro-2-(5-methylthiophen-2-yl)phenyl)ethynyl)pyridin-2-yl)butanoate(40 mg, 0.098 mmol) in THF (4 mL) and methanol (1.0 mL), LiOH (14.10 mg,0.589 mmol) was added and allowed to stir at RT overnight. The reactionmass was concentrated under vacuum, quenched with water (25 mL) andbrine (25 mL) and extracted with ethyl acetate (2×25 mL). Combinedorganic layer was dried over sodium sulphate and concentrated to provide4-(5-((5-fluoro-2-(5-methylthiophen-2-yl)phenyl)ethynyl)pyridin-2-yl)butanoicacid. (0.011 g, 0.029 mmol, 29.5% yield).

¹H NMR (300 MHz, CDCl₃): δ 12.05 (s, 1H), 8.64 (s, 1H), 7.86 (dd, J=2.7Hz, J=6.0 Hz, 1H), 7.67 (q, J=5.7 Hz, 1H), 7.53 (q, J=6.0 Hz, 1H), 7.44(d, J=3.6 Hz, 1H), 7.37-7.32 (m, 2H), 6.88 (d, J=2.7 Hz, 1H), 3.81 (s,3H), 2.79 (t, J=7.2 Hz, 2H), 2.26 (t, J=7.2 Hz, 2H), 1.99-1.88 (s, 2H);MS (m/z): 380.1 (M+1).

Example 44-(5-(5-Fluoro-2-(5-methylthiophen-2-yl)phenethyl)pyridin-2-yl)butanoicacid (Compound 4) Step 4a Synthesis of ethyl4-(5-(5-fluoro-2-(5-methylthiophen-2-yl)phenethyl)pyridin-2-yl)butanoate

To a solution of ethyl4-(5-((5-fluoro-2-(5-methylthiophen-2-yl)phenyl)ethynyl)pyridin-2-yl)butanoate(45 mg, 0.110 mmol) in ethanol (25 mL), Pd/C (1.175 mg, 0.011 mmol) wasadded and the flask was shaken under hydrogen atmosphere at RTovernight. After completion of reaction, it was filtered through celiteand concentrated to provide ethyl4-(5-(5-fluoro-2-(5-methylthiophen-2-yl)phenethyl)pyridin-2-yl)butanoate.(0.040 g, 0.095 mmol, 86% yield).

¹H NMR (300 MHz, CDCl₃): δ 8.27 (s, 1H), 7.43-7.42 (m, 1H), 7.34-7.31(m, 1H), 7.20 (d, J=7.8 Hz, 1H), 6.96-6.63 (m, 2H), 6.73-6.71 (m, 2H),4.14 (q, J=7.2 Hz, 2H), 3.06-2.80 (m, 6H), 2.54 (s, 3H), 2.39 (t, J=7.5Hz, 2H), 2.12-2.07 (m, 2H), 1.27 (t, J=7.2 Hz, 3H); MS (m/z): 411.5(M+1).

Step 4b Synthesis of4-(5-(5-fluoro-2-(5-methylthiophen-2-yl)phenethyl)pyridin-2-yl)butanoicacid

To a solution of ethyl4-(5-(5-fluoro-2-(5-methylthiophen-2-yl)phenethyl)pyridin-2-yl)butanoate(35 mg, 0.085 mmol) in THF (4 mL) and methanol (1.000 mL) was added LiOH(12.22 mg, 0.510 mmol) and allowed to stir at RT overnight. The reactionmass was distilled under vacuum, quenched with water (10 mL) and brine(10 mL) and extracted with ethyl acetate (2×25 mL). Combined organiclayer was dried over sodium sulphate and concentrated to provide4-(5-(5-fluoro-2-(5-methylthiophen-2-yl)phenethyl)pyridin-2-yl)butanoicacid. (0.021 g, 0.054 mmol, 63.4% yield).

¹H NMR (300 MHz, CDCl₃): δ 8.22 (s, 1H), 7.29-7.28 (m, 2H), 7.15 (d,J=8.1 Hz, 1H), 6.93 (d, J=8.7 Hz, 2H), 6.73 (s, 2H), 3.04-2.95 (m, 4H),2.82 (t, J=8.7 Hz, 2H), 2.41 (t, 3=8.2 Hz, 2H), 2.07 (s, 3H), 1.25-1.27(m, 2H); MS (m/z): 384.3 (M+1).

Example 54-(4-(1,1-Difluoro-2-(5-fluoro-2-(5-methylthiophen-2-yl)phenyl)ethyl)phenyl)butanoicacid (Compound 5) Step 5a Synthesis of 2-(3-bromophenyl)acetyl chloride

To a solution 2-(3-bromophenyl)acetic acid (3.5 g, 16.28 mmol) in THF(20 mL), catalytic dimethylformamide was added followed by addition ofoxalyl chloride (1.396 mL, 16.28 mmol), the reaction mixture was allowedto stir for 2 hours followed by concentration under reduced pressure toprovide 2-(3-bromophenyl)acetyl chloride as yellow oil (3.6 g, 15.42mmol, 95% yield).

Step 5b Synthesis of methyl4-(4-(2-(2-bromo-5-fluorophenyl)acetyl)phenyl)butanoate

To a solution of methyl 4-phenylbutanoate (2.2 g, 12.34 mmol) inanhydrous 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (10 ml),Aluminium chloride (1.975 g, 14.81 mmol) was added at −30° C. {obtainedwith dry ice and excess of ethyl acetate}. Reaction mixture was allowedto stir for 30 minutes at this temperature. To the resulting suspension2-(2-bromo-5-fluorophenyl)acetyl chloride (3.10 g, 12.34 mmol) was addedin anhydrous 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (10 mL) andreaction was allowed to stir for 3 hours then at RT overnight. Aftercomplete consumption of starting material, reaction mixture was pouredinto crushed ice and extracted with dichloromethane. Organic layer waswashed with brine, dried over sodium sulphate and concentrated. Theresidue obtained was purified by column chromatography to provide methyl4-(4-(2-(2-bromo-5-fluorophenyl)acetyl)phenyl)butanoate (1.7 g, 4.32mmol, 35.0% yield) as white solid.

¹H NMR (300 MHz, CDCl₃): δ 8.00 (d, J=6.2 Hz, 2H), 7.58 (dd, J=5.4 Hz,8.7 Hz, 1H), 7.34 (d, =8.7 Hz, 2H), 7.04 (dd, =2.7 Hz, 8.7 Hz, 1H), 6.92(t, J=2.7 Hz, 8.4 Hz, 1H), 4.43 (s, 2H), 3.70 (s, 3H), 2.75 (t, =7.5 Hz,2H), 2.37 (t, J=7.50 Hz, 2H), 2.01 (t, J=7.50, 2H); MS (m/z): 395 (M+2).

Step 5c Synthesis of methyl4-(4-(2-(2-bromo-5-fluorobenzyl)-1,3-dithiolan-2-yl)phenyl)butanoate

To a solution of methyl4-(4-(2-(2-bromo-5-fluorophenyl)acetyl)phenyl)butanoate (3 g, 7.63mmol), ethane-1,2-dithiol (0.934 g, 9.92 mmol) in dichloromethane (10mL), Boron trifluoride diethyl etherate (1.257 mL, 9.92 mmol) was added.Reaction was allowed to stir at room temperature overnight. Aftercomplete consumption of starting material, reaction mixture wasconcentrated and purified by column chromatography to provide methyl4-(4-(2-(2-bromo-5-fluorobenzyl)-1,3-dithiolan-2-yl)phenyl)butanoate(3.2 g, 6.82 mmol, 89% yield) as yellow solid.

¹H NMR (300 MHz, CDCl₃): δ 7.56 (d, J=6.2 Hz, 2H), 7.48-7.43 (dd, J=5.4Hz, 8.7 Hz, 1H), 7.13 (d, J=8.7 Hz, 2H), 6.84-6.79 (m, 2H), 3.73 (s,2H), 3.69 (s, 3H), 3.37-3.20 (m, 4H), 2.66 (t, J=7.5 Hz, 2H), 2.34 (t,J=7.50 Hz, 2H), 2.01-1.92 (m, J=7.50, 2H); MS (m/z): 370 (M+1).

Step 5d Synthesis of methyl4-(4-(2-(2-bromo-5-fluorophenyl)acetyl)phenyl)butanoate

To a suspension of 1-iodopyrrolidine-2,5-dione (613 mg, 2.73 mmol) andmethyl4-(4-(2-(2-bromo-5-fluorobenzyl)-1,3-dithiolan-2-yl)phenyl)butanoate(320 mg, 0.682 mmol) in dichloromethane (10 mL) was added pyridine,hydrogen fluoride 30% solution (772 mg, 5.45 mmol) at −78° C. andreaction mixture was allowed to stir at same temperature for 4 hours.The reaction mixture was then allowed to stir overnight at RT afterwhich reaction mass was quenched with addition of saturated sodiumbicarbonate. Reaction mixture was extracted with dichloromethane, washedwith brine, dried over sodium sulphate and concentrated to give crudewhich was purified using column chromatography to provide methyl4-(4-(2-(2-bromo-5-fluorophenyl)acetyl)phenyl)butanoate (10 mg, 0.025mmol, 3.73% yield) along with formation of methyl4-(4-methoxyphenyl)-4-oxobutanoate.

¹H NMR (300 MHz, CDCl₃): δ 7.51 (dd, J=5, 4 Hz, 1H), 7.35 (d, J=8.1 Hz,2H), 7.23 (d, J=8.1 Hz, 2H), 7.12 (dd, J=2.4 Hz, 8.7 Hz, 1H), 6.93 (t,J=2.7 Hz, 8.7 Hz, 1H), 3.69 (s, 3H), 3.61 (t, J=15.6 Hz, HF coupling,2H), 2.72 (t, J=7.5 Hz, 2H), 2.34 (t, =7.5 Hz, 2H), 2.02-1.92 (m, 2H);MS (m/z): 415 (M+1).

Step 5e Synthesis of methyl4-(4-(1,1-difluoro-2-(5-fluoro-2-(5-methylthiophen-2-yl)phenyl)ethyl)phenyl)butanoate

In a mixture of methyl4-(4-(2-(2-bromo-5-fluorophenyl)-1,1-difluoroethyl)phenyl)butanoate(30.6 mg, 0.074 mmol),4,4,5,5-tetramethyl-2-(5-methylthiophen-2-yl)-1,3,2-dioxaborolane (33.0mg, 0.147 mmol) and sodium bicarbonate (12.38 mg, 0.147 mmol) indioxane:water (4:1), tetrakis(triphenylphosphine)palladium(0) (1.064 mg,3.68 μmol) was added. Reaction mixture was heated in microwave at 111°C. for 11 minutes and was quenched with water (10 mL) and extracted withethyl acetate (2×25 mL). Combined organic layer was dried andconcentrated. Crude residue obtained was purified by columnchromatography using 5% ethyl acetate in petroleum ether to providemethyl4-(4-(1,1-difluoro-2-(5-fluoro-2-(5-methylthiophen-2-yl)phenyl)ethyl)phenyl)butanoate.(10 mg, 0.035 mmol, 31.3% yield)

¹H NMR (300 MHz, CDCl₃): δ 7.31 (d, J=5.4 Hz, 1H), 7.22-7.14 (m, 5H),7.03 (dd, J=2.7 Hz, 8.1 Hz, 1H), 6.67 (d, J=2.4 Hz, 1H), 6.51 (d, J=2.7Hz, 1H), 3.69 (s, 3H), 3.60 (t, J=15.6 Hz, 2H), 2.67 (t, J=7.5 Hz, 2H),2.50 (s, 3H), 2.32 (t, J=7.5 Hz, 2H), 2.08-1.92 (m, 2H); MS (m/z): 433.1(M+1).

Step 5f Synthesis of4-(4-(1,1-difluoro-2-(5-fluoro-2-(5-methylthiophen-2-yl)phenyl)ethyl)phenyl)butanoicacid

To solution of methyl4-(4-(1,1-difluoro-2-(5-fluoro-2-(5-methylthiophen-2-(20 mg, 0.046 mmol)in THF:methanol (4:1) was added lithium hydroxide hydrate (185 μL, 0.277mmol) at RT. Reaction mixture was allowed to stir at RT for 4 hours.After complete consumption of starting material, solvent was evaporatedunder reduced pressure and was washed with 5% ethyl acetate in petroleumether. Reaction mixture was then quenched with addition of saturatedammonium chloride and extracted with ethyl acetate. Organic layer wasdried over sodium sulphate and concentrated to provide4-(4-(1,1-difluoro-2-(5-fluoro-2-(5-methylthiophen-2-yl)phenyl)ethyl)phenyl)butanoicacid (13 mg, 0.031 mmol, 67.2% yield).

¹H NMR (300 MHz, CDCl₃): δ 7.31 (d, J=5.4 Hz, 1H), 7.22-7.14 (m, 5H),7.03 (dd, J=2.7 Hz, 8.1 Hz, 1H), 6.67 (d, J=2.4 Hz, 1H), 6.51 (d, J=2.7Hz, 1H), 3.55 (t, J=15.6 Hz, 2H), 2.73 (t, J=7.5 Hz, 2H), 2.50 (s, 3H),2.32 (t, J=7.5 Hz, 2H), 2.08-1.92 (m, 2H); MS (m/z): 419.1 (M+1).

Example 64-(4-(1,1-Difluoro-2-(5-fluoro-2-(5-(1-methylcyclopropyl)thiophen-2-yl)phenyl)ethyl)phenyl)butanoicacid (Compound 6) Step 6a Synthesis of methyl4-(4-(1,1-difluoro-2-(5-fluoro-2-(5-(1-methylcyclopropyl)thiophen-2-yl)phenyl)ethyl)phenyl)butanoate

A solution of methyl4-(4-(2-(2-bromo-5-fluorophenyl)-1,1-difluoroethyl)phenyl)butanoate (70mg, 0.169 mmol),4,4,5,5-tetramethyl-2-(5-(1-methylcyclopropyl)thiophen-2-yl)-1,3,2-dioxaborolane(111 mg, 0.421 mmol), sodium bicarbonate (28.3 mg, 0.337 mmol) indioxane and water (4:1, 4 mL) was degassed under argon. To the resultingmixture tetrakis(triphenylphosphine)palladium(0) (2.435 mg, 8.43 μmol)was added and reaction mixture was heated in microwave at 111° C. for 10min. Reaction mixture was concentrated under reduced pressure and thecrude product was purified by column chromatography to provide methyl4-(4-(1,1-difluoro-2-(5-fluoro-2-(5-(1-methylcyclopropyl)thiophen-2-yl)phenyl)ethyl)phenyl)butanoate(35 mg, 0.074 mmol, 43.9% yield).

¹H NMR (300 MHz, CDCl₃): δ 7.30-7.25 (m, 1H) 7.21-7.14 (m, 5H), 7.01 (t,J=2 Hz, 8 Hz, 1H), 6.65 (d, J=2.2 Hz, 1H), 6.48 (d, J=2.2 Hz, 1H), 3.69(s, 3H), 3.54 (t, J=12.2 Hz, 2H), 2.68 (t, J=6 Hz, 2H), 2.32 (d, J=2.2Hz, 2H), 2.02-1.94 (m, 2H), 1.60 (3H), 0.95-0.94 (m, 2H), 0.88-0.87 (m,2H); MS (m/z): 473.

Step 6b Synthesis of4-(4-(1,1-difluoro-2-(5-fluoro-2-(5-(1-methylcyclopropyl)thiophen-2-yl)phenyl)ethyl)phenyl)butanoicacid

To a solution of methyl 4-(4-(1,1-difluoro-2-(5-fluoro-2-(5-(1-(20 mg,0.042 mmol) in THF (4 mL) and methanol (1 mL), aqueous lithium hydroxide(6.08 mg, 0.254 mmol) was added and allowed to stir at RT for 6 hours.Reaction mixture was concentrated, quenched with dilute ammoniumchloride and extracted with ethyl acetate. Organic layer was dried oversodium sulfate and concentrated. The residue obtained was diluted withethyl acetate (1 mL) followed by precipitation with n-hexane. Theprecipitate was dried under vacuum to obtain desired4-(4-(1,1-difluoro-2-(5-fluoro-2-(5-(1-methylcyclopropyl)thiophen-2-yl)phenyl)ethyl)phenyl)butanoicacid (12 mg, 0.026 mmol, 61.8% yield).

¹H NMR (300 MHz, CDCl₃): δ 7.30-7.14 (m, 6H), 7.20 (t, J=8 Hz, 2.5 Hz,1H), 6.66 (d, =2.2 Hz, 1H), 6.48 (d, J=2.2 Hz, 1H), 3.49 (t, J=13 Hz,2H), 2.70 (t, J=6.2 Hz, 2H), 2.35 (t, J=6.5 Hz, 2H), 2.02-1.94 (m, J=6.4Hz, 2H), 1.27 (s, 3H), 0.95-0.94 (m, 2H), 0.8-0.87 (m, 2H); MS (m/z):459 (M+1).

Example 74-(4-(1,1-Difluoro-2-(4-fluoro-4′-methyl-[1,1′-biphenyl]-2-yl)ethyl)phenyl)butanoicacid (Compound 7) Step 7a Synthesis of methyl4-(4-(1,1-difluoro-2-(4-fluoro-4′-methyl-[1,1′-biphenyl]-2-yl)ethyl)phenyl)butanoate

To a degassed solution of methyl4-(4-(2-(2-bromo-5-fluorophenyl)-1,1-difluoroethyl)phenyl)butanoate (80mg, 0.193 mmol), 4,4,5,5-tetramethyl-2-(p-tolyl)-1,3,2-dioxaborolane (84mg, 0.385 mmol), sodium bicarbonate (32.4 mg, 0.385 mmol) indioxane:water (4 mL:1 mL), tetrakis(triphenylphosphine)palladium(0)(5.57 mg, 0.019 mmol) was added and the reaction mass was heated inmicrowave at 111° C. for 10 minutes. Reaction mixture was thenconcentrated and purified by column chromatography to obtain methyl4-(4-(1,1-difluoro-2-(4-fluoro-4′-methyl-[1,1′-biphenyl]-2-yl)ethyl)phenyl)butanoate.(65 mg, 0.152 mmol, 79% yield)

¹H NMR (300 MHz, CDCl₃): δ 7.20-7.00 (m, 8H), 6.87-6.84 (m, 3H), 3.69(s, 3H), 3.45 (t, J=15.9 Hz, 2H), 2.69 (t, J=7.5 Hz, 2H), 2.40 (s, 3H),2.37 (t, J=7.5 Hz, 2H), 1.99-1.94 (m, 2H); MS (m/z): 449 (M+Na).

Step 7b Synthesis of4-(4-(1,1-difluoro-2-(4-fluoro-4′-methyl-[1,1′-biphenyl]-2-yl)ethyl)phenyl)butanoicacid

To a solution of methyl4-(4-(1,1-difluoro-2-(4-fluoro-4′-methyl-[1,1′-biphenyl]-2-yl)ethyl)phenyl)butanoate(58 mg, 0.136 mmol) in 4 mL of THF:Methanol (4:1) was added lithiumhydroxide monohydrate (453 μL, 0.680 mmol) and the reaction mixture wasallowed to stir at RT overnight. After complete consumption of startingmaterial, solvent was removed under reduced pressure. The reactionmixture was neutralized with saturated ammonium chloride and extractedwith ethyl acetate, dried over sodium sulphate to obtain4-(4-(1,1-difluoro-2-(4-fluoro-4′-methyl-[1,1′-biphenyl]-2-yl)ethyl)phenyl)butanoicacid (56 mg, 0.136 mmol)

¹H NMR (300 MHz, DMSO-d₆): δ 7.16-7.13 (m, 7H), 7.08 (d, J=8.1 Hz, 2H),6.94 (d, J=7.8 Hz, 2H), 3.60 (t, J=14.4 Hz, 2H), 2.62 (t, J=7.2 Hz, 2H),2.34 (s, 3H), 2.23 (t, J=7.2 Hz, 2H), 1.81-1.76 (m, 2H); MS (m/z): 413(M+1).

Example 84-(4-(2-(2-(5-Cyclopropylthiophen-2-yl)-5-fluorophenyl)-1,1-difluoroethyl)phenyl)butanoicacid (Compound 8) Step 8a Synthesis of methyl4-(4-(2-(2-(5-cyclopropylthiophen-2-yl)-5-fluorophenyl)-1,1-difluoroethyl)phenyl)butanoate

To a degassed solution of methyl4-(4-(2-(2-bromo-5-fluorophenyl)-1,1-difluoroethyl)phenyl)butanoate (80mg, 0.193 mmol),2-(5-cyclopropylthiophen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(96 mg, 0.385 mmol), sodium bicarbonate (32.4 mg, 0.385 mmol) in dioxane(4 mL):water (1 mL), tetrakis(triphenylphosphine)palladium(0) (5.57 mg,0.019 mmol) was added and the reaction mixture was heated in microwaveat 111° C. for 10 minutes. Reaction mixture was concentrated andpurified by column chromatography to provide methyl4-(4-(2-(2-(5-cyclopropylthiophen-2-yl)-5-fluorophenyl)-1,1-difluoroethyl)phenyl)butanoate(72 mg, 0.157 mmol, 82% yield).

¹H NMR (300 MHz, DMSO-d₆): δ 7.32-7.30 (m, 1H), 7.22-7.15 (m, 6H), 6.76(d, J=3 Hz, 1H), 6.67 (d, J=3.3 Hz, 1H), 3.70 (t, J=13.5 Hz, 2H), 3.58(s, 3H), 2.64 (t, J=7.5 Hz, 2H), 2.33 (t, J=7.5 Hz, 2H), 2.11-2.10 (m,1H), 1.85-1.80 (m, 2H), 1.02-0.99 (m, 2H), 0.68-0.66 (m, 2H); MS (m/z):481 (M+Na).

Step 8b Synthesis of4-(4-(2-(2-(5-cyclopropylthiophen-2-yl)-5-fluorophenyl)-1,1-difluoroethyl)phenyl)butanoicacid

To a solution of methyl4-(4-(2-(2-(5-cyclopropylthiophen-2-yl)-5-fluorophenyl)-1,1-difluoroethyl)phenyl)butanoate(62 mg, 0.135 mmol) in 4 mL of THF:methanol (4:1) was added lithiumhydroxide monohydrate (451 μL, 0.676 mmol) and the reaction mixture wasallowed to stir at RT overnight. After complete consumption of startingmaterial, solvent was removed under reduced pressure. The reactionmixture was neutralized with saturated ammonium chloride and extractedwith ethyl acetate, dried over sodium sulphate to obtain4-(4-(2-(2-(5-cyclopropylthiophen-2-yl)-5-fluorophenyl)-1,1-difluoroethyl)phenyl)butanoicacid (60 mg, 0.135 mmol).

¹H NMR (300 MHz, DMSO-d₆): δ 12.12 (s, 1H), 7.32-7.15 (m, 7H), 6.75-6.66(m, 2H), 3.70 (t, J=16.8 Hz, 2H), 2.61 (t, J=7.5 Hz, 2H), 2.24-2.11 (m,3H), 1.82-1.77 (m, 2H), 1.01-0.98 (m, 2H), 0.68-0.66 (m, 2H); MS (m/z):443 (M+1).

Example 94-(4-(2-(2-(2,3-Dihydrobenzofuran-5-yl)-5-fluorophenyl)-1,1-difluoroethyl)phenyl)butanoicacid (Compound 9) Step 9a Synthesis of methyl4-(4-(2-(2-(2,3-dihydrobenzofuran-5-yl)-5-fluorophenyl)-1,1-difluoroethyl)phenyl)butanoate

To a degassed solution of methyl4-(4-(2-(2-bromo-5-fluorophenyl)-1,1-difluoroethyl)phenyl)butanoate (80mg, 0.193 mmol), (2,3-dihydrobenzofuran-5-yl)boronic acid (63.2 mg,0.385 mmol), sodium bicarbonate (32.4 mg, 0.385 mmol) in dioxane (4mL):water (1 mL), tetrakis(triphenylphosphine)palladium(0) (5.57 mg,0.019 mmol) was added and the reaction mixture was heated in microwaveat 111° C. for 10 minutes. Reaction mixture was concentrated andpurified by column chromatography to provide methyl4-(4-(2-(2-(2,3-dihydrobenzofuran-5-yl)-5-fluorophenyl)-1,1-difluoroethyl)phenyl)butanoate(58 mg, 0.128 mmol, 66.2% yield).

¹H NMR (300 MHz, CDCl₃): δ 7.42-6.96 (m, 7H), 6.74-6.65 (m, 3H), 4.65(t, J=8.7 Hz, 2H), 3.68 (s, 3H), 3.44 (t, J=15.9 Hz, 2H), 3.23 (t, J=8.7Hz, 2H), 2.69 (t, J=7.5 Hz, 2H), 2.37 9 (t, J=7.5 Hz, 2H), 2.01-1.91 (m,2H); MS (m/z): 477 (M+Na).

Step 9b Synthesis of4-(4-(2-(2-(2,3-dihydrobenzofuran-5-yl)-5-fluorophenyl)-1,1-difluoroethyl)phenyl)butanoicacid

To a solution of methyl4-(4-(2-(2-(2,3-dihydrobenzofuran-5-yl)-5-fluorophenyl)-1,1-difluoroethyl)phenyl)butanoate(58 mg, 0.128 mmol) in 4 mL of THF:Methanol (4:1) was added lithiumhydroxide monohydrate (26.8 mg, 0.638 mmol) and the reaction mixture wasallowed to stir at RT overnight. After complete consumption of startingmaterial, solvent was removed under reduced pressure. The reactionmixture was neutralized with saturated ammonium chloride and extractedwith ethyl acetate, dried over sodium sulphate to provide4-(4-(2-(2-(2,3-dihydrobenzofuran-5-yl)-5-fluorophenyl)-1,1-difluoroethyl)phenyl)butanoicacid (43 mg, 0.098 mmol, 76% yield). ¹H NMR (300 MHz, DMSO-d₆): δ 12.10(s, 1H), 7.21-7.13 (m, 5H), 7.07-7.04 (m, 2H), 6.72 (s, 3H), 4.58 (t,J=8.7 Hz, 2H), 3.54 (t, J=16.5 Hz, 2H), 3.19 (t, J=8.7 Hz, 2H), 2.63 (t,J=7.5 Hz, 2H), 2.23 (t, J=7.5 Hz, 2H), 1.81-1.76 (m, 2H); MS (m/z): 439(M−1).

Example 104-(4-(2-(4′-Cyclopropyl-4-fluoro-[1,1′-biphenyl]-2-yl)-1,1-difluoroethyl)phenyl)butanoicacid (Compound 10) Step 10a Synthesis of methyl4-(4-(2-(4′-cyclopropyl-4-fluoro-[1,1′-biphenyl]-2-yl)-1,1-difluoroethyl)phenyl)butanoate

To a degassed solution of methyl4-(4-(2-(2-bromo-5-fluorophenyl)-1,1-difluoroethyl)phenyl)butanoate (80mg, 0.193 mmol), sodium bicarbonate (32.4 mg, 0.385 mmol),(4-cyclopropylphenyl)boronic acid (62.4 mg, 0.385 mmol) in dioxane (4mL) and water (1 mL), tetrakis(triphenylphosphine)palladium(0) (5.57 mg,0.019 mmol) was added and the reaction mass was heated in microwave at111° C. for 10 minutes. Reaction mixture was concentrated and purifiedby column chromatography to provide methyl4-(4-(2-(4′-cyclopropyl-4-fluoro-[1,1′-biphenyl]-2-yl)-1,1-difluoroethyl)phenyl)butanoate(73 mg, 0.161 mmol, 84% yield).

¹H NMR (300 MHz, CDCl₃): δ 7.19-6.96 (m, 9H), 6.86 (d, J=8.1 Hz, 2H),3.69 (s, 3H), 3.45 (t, J=15.9 Hz, 2H), 2.69 (t, J=7.2 Hz, 2H), 2.37 (t,J=7.2 Hz, 2H), 2.01-1.89 (m, 3H), 1.06-0.99 (m, 2H), 0.77-0.72 (m, 2H);MS (m/z): 475 (M+Na).

Step 10b Synthesis of4-(4-(2-(4′-cyclopropyl-4-fluoro-[1,1′-biphenyl]-2-yl)-1,1-difluoroethyl)phenyl)butanoicacid

To a solution of methyl4-(4-(2-(4′-cyclopropyl-4-fluoro-[1,1′-biphenyl]-2-yl)-1,1-difluoroethyl)phenyl)butanoate(70 mg, 0.155 mmol) in 4 mL of THF:Methanol (4:1) was added lithiumhydroxide monohydrate (32.5 mg, 0.773 mmol) and the reaction mixture wasallowed to stir at RT overnight. After complete consumption of startingmaterial, solvent was removed under reduced pressure. The reactionmixture was neutralized with saturated ammonium chloride and extractedwith ethyl acetate, dried over sodium sulphate to provide4-(4-(2-(4′-cyclopropyl-4-fluoro-[1,1′-biphenyl]-2-yl)-1,1-difluoroethyl)phenyl)butanoicacid (46 mg, 0.105 mmol, 67.8% yield).

¹H NMR (300 MHz, DMSO-d₆): δ 12.18 (s, 1H), 7.19-7.05 (m, 9H), 6.92 (d,J=7.4 Hz, 2H), 3.55 (t, J=16.5 Hz, 2H), 2.62 (t, J=7.2 Hz, 2H), 2.23 (t,J=7.2 Hz, 2H), 1.94-1.76 (m, 3H), 0.98-0.96 (m, 2H), 0.71-0.69 (m, 2H);MS (m/z): 437 (M+1).

Example 114-(4-((2-(5-(1-Cyanocyclopropyl)thiophen-2-yl)-5-fluorophenyl)ethynyl)phenyl)butanoicacid (Compound 11) Step 11a Synthesis of1-(5-(4-fluoro-2-formylphenyl)thiophen-2-yl)cyclopropanecarbonitrile

To a degassed solution of5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde(411 mg, 1.644 mmol), 1-(5-bromothiophen-2-yl)cyclopropanecarbonitrile(250 mg, 1.096 mmol) and sodium bicarbonate (184 mg, 2.192 mmol) indioxane (4 mL):water (1 mL), tetrakis(triphenylphosphine)palladium(0)(31.7 mg, 0.110 mmol) was added and reaction mass was heated inmicrowave at 111° C. for 10 minutes. The reaction mixture was thenconcentrated and purified by column chromatography to provide1-(5-(4-fluoro-2-formylphenyl)thiophen-2-yl)cyclopropanecarbonitrile(297 mg, 1.095 mmol).

¹H NMR (300 MHz, DMSO-d₆): δ 10.13 (s, 1H), 7.72-7.71 (m, 1H), 7.69-7.68(m, 2H), 6.52-6.51 (m, 2H), 1.85 (s, 2H), 1.53 (s, 2H); MS (m/z): 272(M+1).

Step 11b Synthesis of1-(5-(2-ethynyl-4-fluorophenyl)thiophen-2-yl)cyclopropanecarbonitrile

To a solution of1-(5-(4-fluoro-2-formylphenyl)thiophen-2-yl)cyclopropanecarbonitrile(0.050 g, 0.184 mmol) in dry methanol (5 ml) was added potassiumcarbonate (0.051 g, 0.369 mmol) and dimethyl(1-diazo-2-oxopropyl)phosphonate (0.531 mL, 0.221 mmol) at RT underargon, and the mixture was stirred at RT for 1 hour. The reaction wasquenched with brine (15 mL), and the mixture extracted with ethylacetate (2×25 mL). The combined organic layer was washed with brine (30mL), dried over sodium sulfate, Solvent was removed under reducedpressure to give crude which was purified by column chromatography togive1-(5-(2-ethynyl-4-fluorophenyl)thiophen-2-yl)cyclopropanecarbonitrile(0.035 g, 0.131 mmol, 71.0% yield) as liquid.

¹H NMR (300 MHz, CDCl₃): δ 7.46-7.41 (m, 1H), 7.45-7.41 (m, 1H),7.37-7.35 (m, 1H), 7.32-7.31 (m, 1H), 7.13-7.04 (m, 1H), 3.32 (s, 1H),1.80-1.78 (m, 2H), 1.51-1.48 (m, 2H); MS (m/z): 268 (M+1).

Step 1.1c Synthesis of methyl4-(4-((2-(5-(1-cyanocyclopropyl)thiophen-2-yl)-5-fluorophenyl)ethynyl)phenyl)butanoate

To a solution of methyl 4-(4-iodophenyl)butanoate (150 mg, 0.493 mmol),1-(5-(2-ethynyl-4-fluorophenyl)thiophen-2-yl)cyclopropanecarbonitrile(158 mg, 0.592 mmol) in DMF, triethylamine (0.207 ml, 1.480 mmol) wasadded and the reaction mixture was degassed with argon andbis(triphenylphosphine)palladium(II) dichloride (34.6 mg, 0.049 mmol)added followed by addition of copper(I) iodide (9.39 mg, 0.049 mmol).Reaction was stirred at 85° C. for 4 hours. After completion ofreaction, reaction mass was concentrated to give crude, which waspurified column chromatography to providemethyl4-(4-((2-(5-(1-cyanocyclopropyl)thiophen-2-yl)-5-fluorophenyl)ethynyl)phenyl)butanoate(185 mg, 0.417 mmol, 85% yield).

¹H NMR (300 MHz, CDCl₃): δ 7.51-7.48 (m, 1H), 7.45-7.42 (m, 2H), 7.38(dd, J=3.6, 8.4 Hz, 1H), 7.22 (d, 3=7.8 Hz, 2H), 7.08-7.05 (m, 3H), 3.69(s, 3H), 2.72 (t, J=7.2 Hz, 2H), 2.38 (t, J=7.5 Hz, 2H), 2.03-1.96 (m,2H), 1.83-1.79 (m, 2H), 1.53-1.48 (m, 2H); MS (m/z): 444 (M+1).

Step 11d Synthesis of4-(4-((2-(5-(1-cyanocyclopropyl)thiophen-2-yl)-5-fluorophenyl)ethynyl)-phenyl)butanoic acid

To a solution of methyl4-(4-((2-(5-(1-cyanocyclopropyl)thiophen-2-yl)-5-fluorophenyl)ethynyl)phenyl)butanoate(30 mg, 0.068 mmol) in 4 mL of THF:methanol (4:1), LiOH.H₂O (225 μL,0.338 mmol) was added and the reaction mixture was allowed to stir at RTovernight. After complete consumption of starting material, solvent wasremoved under reduced pressure. The reaction mixture was neutralizedwith saturated ammonium chloride, extracted with ethyl acetate and driedover sodium sulphate to get4-(4-((2-(5-(1-cyanocyclopropyl)thiophen-2-yl)-5-fluorophenyl)ethynyl)phenyl)butanoicacid (25 mg, 0.058 mmol, 86% yield).

¹H NMR (300 MHz, DMSO-d₆): δ 7.73-7.70 (m, 1H), 7.51-7.49 (m, 4H),7.34-7.27 (m, 3H), 7.15 (d, J=3.6 Hz, 1H), 2.63 (t, 3=7.2 Hz, 2H), 2.24(t, J=7.5 Hz, 2H), 1.86-1.80 (m, 2H), 1.83-1.79 (m, 2H), 1.53-1.48 (m,2H); MS (m/z): 430.1 (M+1).

Compounds 12 to 22 were prepared analogous to Compounds 1 to 11 and areprovided in Table 1

TABLE 1 Compound 12 4-(4-(5-fluoro-2-(4,5,6,7-tetrahydrobenzo[d]thiazol-2- yl)phenethyl)phenyl)butanoic acid

Compound 13 4-(4-(2-(5-cyclopropylthiophen-2-yl)-5-fluorophenethyl)phenyl)butanoic acid

Compound 14 4-(4-(5-fluoro-2-(5-(1- methylcyclopropyl)thiophen-2-yl)styryl)phenyl)butanoic acid

Compound 15 4-(4-(2-(5-(1- cyanocyclopropyl)thiophen-2-yl)-5-fluorostyryl)phenyl)butanoic acid

Compound 16 4-(4-(5-fluoro-2-(4,5,6,7- tetrahydrobenzo[b]thiophen-2-yl)styryl)phenyl)butanoic acid

Compound 17 4-(4-(5-fluoro-2-(4,5,6,7- tetrahydrobenzo[d]thiazol-2-yl)styryl)phenyl)butanoic acid

Compound 18 4-(4-((2-(5-cyclopropylthiophen-2-yl)-5-fluorophenyl)ethynyl)phenyl)butanoic acid

Compound 19 4-(4-((5-fluoro-2-(4,5,6,7- tetrahydrobenzo[d]thiazol-2-yl)phenyl)ethynyl)phenyl)butanoic acid

Compound 20 4-(4-(1,1-difluoro-2-(5-fluoro-2-(6- methoxypyridin-3-yl)phenyl)ethyl)phenyl)butanoic acid

Compound 21 4-(4-(1,1-difluoro-2-(5-fluoro-2-(5,6,7,8-tetrahydronaphthalen-2- yl)phenyl)ethyl)phenyl)butanoic acid

Compound 22 4-(4-(2-(2-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-5-fluorophenyl)-1,1- difluoroethyl)phenyl)butanoic acid

Biological Assays

Representative compounds of Formula (I) of the present invention(referred to as test compounds) were tested for their activity using theassays and the methods described below.

Beta (β) arrestin 2 Interaction Assay (BRET assay) was performed usingCHO-K1 cells stably expressing the GPR120L (Long Isoform) receptor usingβ-galactosidase (Beta gal) enzyme fragment complementation assay. Themeasurement of GPR120 activation upon agonist activation was directlyprovided by β-arrestin recruitment. One day before the β-arrestin 2assay, CHO-K1 cells were seeded and incubated overnight at 37° C. in a5% CO₂ humidified atmosphere. Cells were treated with the test compoundsin various concentrations ranging from 30 μM to 1 nM and incubated for 2hours for GPCR (GPR120) activation. Extent of Arrestin recruitment wasmeasured by adding detection reagents for Beta gal complementationassay, and was further incubated for 1 hour. The chemiluminescent signalwas detected on Polar Star (BMG Labtech). The dose-response curve wasanalyzed using Sigma Plot/Graph Pad. The EC₅₀ (concentration of the testcompounds where 50% of compounds' maximal activity is observed) valueswere calculated from the dose-response curve. Similar procedure wasfollowed for HEK 293 cells and results obtained are tabulated in Table2.

TABLE 2 EC₅₀ values of compounds of Examples Compound No. EC₅₀ (nM)Compound 3 + Compound 5 +++ Compound 6 ++ Compound 11 ++ Compound 12 +++Compound 13 ++ Compound 14 +++ Compound 18 +++ Compound 20 +++ The EC₅₀(nM) values of the compounds are presented in Table 1 wherein: +++corresponds to EC₅₀ ranging from 50 nM to 500 nM; ++ corresponds to EC₅₀ranging from 500 nM to 5000 nM; + corresponds to EC₅₀ ranging from 5000nM to 10000 nM; Conclusion: The EC₅₀ values determined for the compoundsof the present invention is indicative of GPR120 agonist activity of thecompounds of the present invention.

1. A compound of formula (I);

wherein, Ring A is 3- to 10-membered cycloalkyl, 5- to 12-memberedheterocycloalkyl; (C₆-C₁₀)aryl or 5- to 12-membered heteroaryl; whereinthe heterocycloalkyl and the heteroaryl contain 1, 2, 3 or 4 heteroatomsindependently selected from the group consisting of N, O and S; Ring Band Ring C are independently selected from (C₆-C₁₀)aryl or 5- to12-membered heteroaryl containing 1, 2 or 3 heteroatoms independentlyselected from the group consisting of N, O and S; X is

wherein

represents a point of attachment; R is hydrogen or (C₁-C₆)alkyl; R¹, R²and R³ at each occurrence are independently selected from the groupconsisting of hydrogen, halogen, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, 3- to10-membered cycloalkyl and 5- to 12-membered heterocycloalkyl; or two R¹are combined together with Ring A to form a 3- to 6-membered cycloalkylor 5- to 12-membered heterocycloalkyl; R⁴ and R⁷ are independentlyselected from hydrogen or (C₁-C₆)alkyl; R⁵ and R⁶ are independentlyselected from the group consisting of hydrogen, halogen and(C₁-C₆)alkyl; m, n and p are each integer independently selected from 1,2 and 3; wherein, (C₁-C₆)alkyl is unsubstituted or substituted with oneor more groups independently selected from the group consisting ofhalogen, hydroxy, cyano, nitro, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl,—O(C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, (C₆-C₁₀)aryl, heterocycloalkyl andheteroaryl; cycloalkyl is a 3- to 10-membered ring, which isunsubstituted or substituted with one or more groups independentlyselected from the group consisting of (C₁-C₆)alkyl, halogen, hydroxy,—O—(C₁-C₆)alkyl, (C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, heterocycloalkyl,heteroaryl, amino and cyano; heteroaryl is a 5- to 12-membered ring,which is unsubstituted or substituted with one or more groupsindependently selected from the group consisting of (C₁-C₆)alkyl,halogen, hydroxy, —O—(C₁-C₆)alkyl, (C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl,heterocycloalkyl, heteroaryl, amino and cyano; heterocycloalkyl is a 5-to 12-membered ring, which is unsubstituted or substituted with one ormore groups independently selected from the group consisting of(C₁-C₆)alkyl, halogen, hydroxy, —O—(C₁-C₆)alkyl, (C₃-C₁₀)cycloalkyl,(C₆-C₁₀)aryl, heterocycloalkyl, heteroaryl, amino and cyano; halogen ischlorine, bromine, iodine or fluorine; or a stereoisomer, a tautomer, apharmaceutically acceptable salt, a pharmaceutically acceptable solvate,a prodrug, a polymorph, N-oxide, S-oxide, or a carboxylic acid isosterethereof.
 2. The compound of Formula (I) according to claim 1, whereinRing A is unsubstituted or substituted 3- to 10-membered cycloalkyl orunsubstituted or substituted 5- to 12-membered heterocycloalkylcontaining 1, 2, 3 or 4 heteroatoms independently selected from thegroup consisting of N, O and S or unsubstituted or substituted(C₆-C₁₀)aryl or 5- to 12-membered heteroaryl containing 1, 2, 3 or 4heteroatoms independently selected from the group consisting of N, O andS or unsaturated or partially unsaturated (C₆-C₁₀)aryl or unsaturated orpartially unsaturated 5- to 12-membered heteroaryl.
 3. The compound ofFormula (I) according to claim 1, wherein Ring A is

wherein

represents a point of attachment to Ring B.
 4. The compound of Formula(I) according to claim 1, wherein Ring B is unsubstituted or substituted(C₆-C₁₀)aryl or 5- to 12-membered heteroaryl containing 1, 2 or 3heteroatoms independently selected from the group consisting of N, O andS.
 5. The compound of Formula (I) according to claim 4, wherein Ring Bis unsubstituted or substituted phenyl.
 6. The compound of Formula (I)according to claim 5, wherein Ring B is unsubstituted or substitutedphenyl and R² is located at para position to Ring A and n is
 1. 7. Thecompound of Formula (I) according to claim 6, wherein Ring B is phenyland R² is halogen located at para position to Ring A and n is
 1. 8. Thecompound of Formula (I) according to claim 1, wherein Ring C isunsubstituted or substituted (C₆-C₁₀)aryl or 5- to 12-memberedheteroaryl containing 1, 2 or 3 heteroatoms independently selected fromthe group consisting of N, O and S.
 9. The compound of Formula (I)according to claim 8, wherein Ring C is unsubstituted or substitutedphenyl, or unsubstituted or substituted 5- to 6-membered heteroaryl. 10.The compound of Formula (I) according to claim 1, wherein two R¹ arecombined together with Ring A to form a 3- to 6-membered cycloalkyl or5- to 12-membered heterocycloalkyl.
 11. The compound of Formula (I)according to claim 1, wherein Ring B is unsubstituted or substitutedphenyl; Ring C is unsubstituted or substituted phenyl, or unsubstitutedor substituted 5- to 6-membered heteroaryl; R² is located at paraposition to Ring A; R³ is hydrogen; and m & n are
 1. 12. The compound ofFormula (I) according to claim 1, wherein Ring B is unsubstituted orsubstituted phenyl; Ring C is unsubstituted or substituted phenyl, R² ishalogen located at para position to Ring A; R³ is hydrogen; and m & nare
 1. 13. The compound of Formula (I) according to claim 1, whereinRing B is unsubstituted or substituted phenyl; Ring C is unsubstitutedor substituted 5- to 6-membered heteroaryl; R² is located at paraposition to Ring A; R³ is hydrogen; and m & n are
 1. 14. The compound ofFormula (I) according to claim 1, wherein Ring B is unsubstituted orsubstituted (C₆-C₁₀)aryl or 5- to 12-membered heteroaryl; Ring C isunsubstituted or substituted (C₆-C₁₀)aryl or 5- to 12-memberedheteroaryl and Ring A is saturated or partially unsaturated 5- to12-membered bicyclic heteroaryl or 5- to 12-membered bicyclicheterocycloalkyl.
 15. The compound of Formula (I) according to claim 1,wherein Ring B is unsubstituted or substituted (C₆-C₁₀)aryl or 5- to12-membered heteroaryl; Ring C is unsubstituted or substituted(C₆-C₁₀)aryl or 5- to 12-membered heteroaryl; Ring A is 5- to 6-memberedmonocyclic heteroaryl and R¹ is 3- to 10-membered cycloalkyl.
 16. Acompound of Formula IA;

wherein, Ring A is 3- to 10-membered cycloalkyl, 5- to 12-memberedheterocycloalkyl; (C₆-C₁₀)aryl or 5- to 12-membered heteroaryl, whereinthe heterocycloalkyl and the heteroaryl contain 1, 2, 3 or 4 heteroatomsindependently selected from the group consisting of N, O and S; Ring Band Ring C are independently selected from (C₆-C₁₀)aryl or 5- to12-membered heteroaryl containing 1, 2 or 3 heteroatoms independentlyselected from the group consisting of N, O and S; R is hydrogen or(C₁-C₆)alkyl; R¹, R² and R³ at each occurrence are independentlyselected from the group consisting of hydrogen, halogen, (C₁-C₆)alkyl,halo(C₁-C₆)alkyl, 3- to 10-membered cycloalkyl and 5- to 12-memberedheterocycloalkyl; m, n and p are each an integer independently selectedfrom 1, 2 and 3; wherein, (C₁-C₆)alkyl is unsubstituted or substitutedwith one or more groups independently selected from the group consistingof halogen, hydroxy, cyano, nitro, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl,—O(C₁-C₆)alkyl, (C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, heterocycloalkyl andheteroaryl; cycloalkyl is a 3- to 10-membered ring, which isunsubstituted or substituted with one or more groups independentlyselected from the group consisting of (C₁-C₆)alkyl, halogen, hydroxy,—O—(C₁-C₆)alkyl, (C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, heterocycloalkyl,heteroaryl, amino and cyano; heteroaryl is a 5- to 12-membered ring,which is unsubstituted or substituted with one or more groupsindependently selected from the group consisting of (C₁-C₆)alkyl,halogen, hydroxy, —O—(C₁-C₆)alkyl, (C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl,heterocycloalkyl, heteroaryl, amino and cyano; heterocycloalkyl is a 5-to 12-membered ring, which is unsubstituted or substituted with one ormore groups independently selected from the group consisting of(C₁-C₆)alkyl, halogen, hydroxy, —O—(C₁-C₆)alkyl, (C₃-C₁₀)cycloalkyl,(C₆-C₁₀)aryl, heterocycloalkyl, heteroaryl, amino and cyano; halogen ischlorine, bromine, iodine or fluorine; or a stereoisomer, a tautomer, apharmaceutically acceptable salt, a pharmaceutically acceptable solvate,a prodrug, a polymorph, N-oxide, S-oxide, or a carboxylic acid isosterethereof.
 17. A compound of Formula IB;

Ring A is 3- to 10-membered cycloalkyl, 5- to 12-memberedheterocycloalkyl; (C₆-C₁₀)aryl or 5- to 12-membered heteroaryl, whereinthe heterocycloalkyl and the heteroaryl contain 1, 2, 3 or 4 heteroatomsindependently selected from the group consisting of N, O and S; Ring Band Ring C are independently selected from the group consisting of(C₆-C₁₀)aryl or 5- to 12-membered heteroaryl containing 1, 2 or 3heteroatoms independently selected from the group consisting of N, O andS; R is hydrogen or (C₁-C₆)alkyl; R¹, R² and R³ at each occurrence areindependently selected from the group consisting of hydrogen, halogen,(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, 3- to 10-membered cycloalkyl, and 5- to12-membered heterocycloalkyl; R⁴ is independently selected from hydrogenor (C₁-C₆)alkyl; R⁵ is independently selected from hydrogen, halogen or(C₁-C₆)alkyl; m, n and p are each an integer independently selected from1, 2 and 3; wherein, (C₁-C₆)alkyl is unsubstituted or substituted withone or more groups independently selected from the group consisting ofhalogen, hydroxy, cyano, nitro, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl,—O(C₁-C₆)alkyl, (C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, heterocycloalkyl andheteroaryl; cycloalkyl is a 3- to 10-membered ring, which isunsubstituted or substituted with one or more groups independentlyselected from the group consisting of (C₁-C₆)alkyl, halogen, hydroxy,—O—(C₁-C₆)alkyl, (C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, heterocycloalkyl,heteroaryl, amino and cyano; heteroaryl is a 5- to 12-membered ring,which is unsubstituted or substituted with one or more groupsindependently selected from the group consisting of (C₁-C₆)alkyl,halogen, hydroxy, —O—(C₁-C₆)alkyl, (C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl,heterocycloalkyl, heteroaryl, amino and cyano; heterocycloalkyl is a 5-to 12-membered ring, which is unsubstituted or substituted with one ormore groups independently selected from the group consisting of(C₁-C₆)alkyl, halogen, hydroxy, —O—(C₁-C₆)alkyl, (C₃-C₁₀)cycloalkyl,(C₆-C₁₀)aryl, heterocycloalkyl, heteroaryl, amino and cyano; halogen isselected from chlorine, bromine, iodine or fluorine; or a stereoisomer,a tautomer, a pharmaceutically acceptable salt, a pharmaceuticallyacceptable solvate, a prodrug, a polymorph, N-oxide, S-oxide, or acarboxylic acid isostere thereof.
 18. A compound of Formula IC;

wherein, Ring A is 3- to 10-membered cycloalkyl, 5- to 12-memberedheterocycloalkyl; (C₆-C₁₀)aryl or 5- to 12-membered heteroaryl, whereinthe heterocycloalkyl and the heteroaryl contain 1, 2, 3 or 4 heteroatomsindependently selected from the group consisting of N, O and S; Ring Band Ring C are independently selected from the group consisting of(C₆-C₁₀)aryl or 5- to 12-membered heteroaryl containing 1, 2 or 3heteroatoms independently selected from the group consisting of N, O andS; R is hydrogen or (C₁-C₆)alkyl; R¹, R² and R³ at each occurrence isindependently selected from the group consisting of hydrogen, halogen,(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, 3- to 10-membered cycloalkyl and 5- to12-membered heterocycloalkyl; R⁴ and R⁷ are independently selected fromhydrogen or (C₁-C₆)alkyl; R⁵ and R⁶ are independently selected from thegroup consisting of hydrogen, halogen and (C₁-C₆)alkyl; m, n and p areeach an integer independently selected from 1, 2 or 3; wherein,(C₁-C₆)alkyl is unsubstituted or substituted with one or more groupsindependently selected from the group consisting of halogen, hydroxy,cyano, nitro, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, —O(C₁-C₆)alkyl,(C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, heterocyclyl and heteroaryl;cycloalkyl is a 3- to 10-membered ring, which is unsubstituted orsubstituted with one or more groups independently selected from thegroup consisting of (C₁-C₆)alkyl, halogen, hydroxy, —O—(C₁-C₆)alkyl,(C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, heterocyclyl, heteroaryl, amino andcyano; heteroaryl is a 5- to 12-membered ring, which is unsubstituted orsubstituted with one or more groups independently selected from thegroup consisting of (C₁-C₆)alkyl, halogen, hydroxy, —O—(C₁-C₆)alkyl,(C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, heterocycloalkyl, heteroaryl, aminoand cyano; heterocycloalkyl is a 5- to 12-membered ring, which isunsubstituted or substituted with one or more groups independentlyselected from the group consisting of (C₁-C₆)alkyl, halogen, hydroxy,—O—(C₁-C₆)alkyl, (C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, heterocycloalkyl,heteroaryl, amino and cyano; halogen is selected from chlorine, bromine,iodine or fluorine; or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, a pharmaceutically acceptable solvate, a prodrug, apolymorph, N-oxide, S-oxide, or a carboxylic acid isostere thereof. 19.A compound of Formula ID;

wherein, Ring A is 3- to 10-membered cycloalkyl, 5- to 12-memberedheterocycloalkyl; (C₆-C₁₀)aryl or 5- to 12-membered heteroaryl; whereinthe heterocycloalkyl and the heteroaryl contain 1, 2, 3 or 4 heteroatomsindependently selected from the group consisting of N, O and S; Ring Band Ring C are independently selected from (C₆-C₁₀)aryl or 5- to12-membered heteroaryl containing 1, 2 or 3 heteroatoms independentlyselected from the group consisting of N, O and S; X is

wherein

represents a point of attachment; R is hydrogen or (C₁-C₆)alkyl; R¹, R²and R³ at each occurrence are independently selected from the groupconsisting of hydrogen, halogen, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, 3- to10-membered cycloalkyl and 5- to 12-membered heterocycloalkyl; R⁴ and R⁷are independently selected from the group consisting of hydrogen and(C₁-C₆)alkyl; R⁵ and R⁶ are independently selected from the groupconsisting of hydrogen, halogen and (C₁-C₆)alkyl; m, n and p are eachinteger independently selected from 1, 2 and 3; wherein, (C₁-C₆)alkyl isunsubstituted or substituted with one or more groups independentlyselected from the group consisting of halogen, hydroxy, cyano, nitro,(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, —O(C₁-C₆)alkyl, (C₃-C₈)cycloalkyl,(C₆-C₁₀)aryl, heterocycloalkyl and heteroaryl; cycloalkyl is a 3- to10-membered ring, which is unsubstituted or substituted with one or moregroups independently selected from the group consisting of (C₁-C₆)alkyl,halogen, hydroxy, —O—(C₁-C₆)alkyl, (C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl,heterocycloalkyl, heteroaryl, amino and cyano; heteroaryl is a 5- to12-membered ring, which is unsubstituted or substituted with one or moregroups independently selected from the group consisting of (C₁-C₆)alkyl,halogen, hydroxy, —O—(C₁-C₆)alkyl, (C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl,heterocycloalkyl, heteroaryl, amino and cyano; heterocycloalkyl is a 5-to 12-membered ring, which is unsubstituted or substituted with one ormore groups independently selected from the group consisting of(C₁-C₆)alkyl, halogen, hydroxy, —O—(C₁-C₆)alkyl, (C₃-C₁₀)cycloalkyl,(C₆-C₁₀)aryl, heterocycloalkyl, heteroaryl, amino and cyano; halogen ischlorine, bromine, iodine or fluorine; or a stereoisomer, a tautomer, apharmaceutically acceptable salt, a pharmaceutically acceptable solvate,a prodrug, a polymorph, N-oxide, S-oxide, or a carboxylic acid isosterethereof.
 20. The compound according to claim 1, wherein the compound isselected from:4-(5-((5-Fluoro-2-(6-methoxypyridin-3-yl)phenyl)ethynyl)pyridin-2-yl)butanoicacid;4-(5-(5-Fluoro-2-(6-methoxypyridin-3-yl)phenethyl)pyridin-2-yl)butanoicacid;4-(5-((5-Fluoro-2-(5-methylthiophen-2-yl)phenyl)ethynyl)pyridin-2-yl)butanoicacid;4-(5-(5-Fluoro-2-(5-methylthiophen-2-yl)phenethyl)pyridin-2-yl)butanoicacid;4-(4-(1,1-Difluoro-2-(5-fluoro-2-(5-methylthiophen-2-yl)phenyl)ethyl)phenyl)butanoicacid;4-(4-(1,1-Difluoro-2-(5-fluoro-2-(5-(1-methylcyclopropyl)thiophen-2-yl)phenyl)ethyl)-phenyl)butanoicacid;4-(4-(1,1-Difluoro-2-(4-fluoro-4′-methyl-[1,1′-biphenyl]-2-yl)ethyl)phenyl)butanoicacid,4-(4-(2-(2-(5-Cyclopropylthiophen-2-yl)-5-fluorophenyl)-1,1-difluoroethyl)phenyl)-butanoicacid;4-(4-(2-(2-(2,3-Dihydrobenzofuran-5-yl)-5-fluorophenyl)-1,1-difluoroethyl)phenyl)-butanoicacid;4-(4-(2-(4′-Cyclopropyl-4-fluoro-[1,1′-biphenyl]-2-yl)-1,1-difluoroethyl)phenyl)butanoicacid;4-(4-((2-(5-(1-Cyanocyclopropyl)thiophen-2-yl)-5-fluorophenyl)ethynyl)phenyl)-butanoicacid;4-(4-(5-fluoro-2-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)phenethyl)phenyl)butanoicacid;4-(4-(2-(5-cyclopropylthiophen-2-yl)-5-fluorophenethyl)phenyl)butanoicacid;4-(4-(5-fluoro-2-(5-(1-methylcyclopropyl)thiophen-2-yl)styryl)phenyl)butanoicacid;4-(4-(2-(5-(1-cyanocyclopropyl)thiophen-2-yl)-5-fluorostyryl)phenyl)butanoicacid;4-(4-(5-fluoro-2-(4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)styryl)phenyl)butanoicacid;4-(4-(5-fluoro-2-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)styryl)phenyl)butanoicacid;4-(4-((2-(5-cyclopropylthiophen-2-yl)-5-fluorophenyl)ethynyl)phenyl)butanoicacid;4-(4-((5-fluoro-2-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)phenyl)ethynyl)phenyl)-butanoicacid;4-(4-(1,1-difluoro-2-(5-fluoro-2-(6-methoxypyridin-3-yl)phenyl)ethyl)phenyl)butanoicacid;4-(4-(1,1-difluoro-2-(5-fluoro-2-(5,6,7,8-tetrahydronaphthalen-2-yl)phenyl)ethyl)phenyl)butanoicacid; and4-(4-(2-(2-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-5-fluorophenyl)-1,1-difluoroethyl)phenyl)butanoicacid; or a stereoisomer, a tautomer, a pharmaceutically acceptable salt,a pharmaceutically acceptable solvate, a prodrug, a polymorph, N-oxide,S-oxide, or a carboxylic acid isostere thereof.
 21. A pharmaceuticalcomposition comprising a therapeutically effective amount of thecompound according to claim 1, or a stereoisomer, a tautomer, apharmaceutically acceptable salt or a pharmaceutically acceptablesolvate thereof; and at least one pharmaceutically acceptable carrier orexcipient.
 22. A method for the treatment or prophylaxis of a disease ora disorder mediated by GPR120 comprising administering to a subject inneed thereof; a therapeutically effective amount of the compoundsaccording to claim 1, or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt or a pharmaceutically acceptable solvate thereof. 23.The method according to claim 22, wherein the disease or disordermediated by GPR120 is a metabolic disorder or an inflammatory disorder.24. (canceled)
 25. A compound according to claim 1 or a stereoisomer, atautomer, a pharmaceutically acceptable salt or a pharmaceuticallyacceptable solvate thereof; for use in the treatment or prophylaxis of adisease or a disorder mediated by GPR120.
 26. (canceled)